BONE AND DIABETES (AV SCHWARTZ AND P VESTERGAARD, SECTION EDITORS)

Diabetes Medications and Bone

Andrew Grey

Published online: 30 November 2014# Springer Science+Business Media New York 2014

Abstract Type 2 diabetes mellitus (T2DM) is a commonchronic disease that may be associated with an increased riskof fracture. Evidence that thiazolidinediones (TZDs) increasefracture risk in women with T2DM has focused attention onthe skeletal effects of treatments for diabetes. Only scant, low-quality evidence is available for non-TZD diabetes medica-tions and bone health, but it suggests that there are no clini-cally important effects.

Keywords Diabetes .Osteoporosis .Fracture .Bonedensity .

Drug treatments

Introduction

The incidence of type 2 diabetes mellitus (T2DM) is rapidlyincreasing internationally. Consequently, the prevention andmanagement of the disease and its many complications hasbecome an important public health issue. A body of epidemi-ological evidence suggests that fracture risk is increased inpeople with T2DM [1, 2]. The mechanism by which skeletalfragility is increased in T2DM is not understood, but may berelated to an increased risk of falls and/or as yetuncharacterized abnormalities of bone structure [3]. Whilethe increase in risk is generally modest (1.2–1.8-fold com-pared to non-diabetics), the high prevalence of T2DM meansthat associated fractures are an important clinical problem. It istherefore important to consider the effects of diabetes treat-ments on bone health.

Methodology

Note In compiling this review, the author searched Medlinefor relevant literature using search terms that included indi-vidual drug names or the names of drug classes and “bone” or“osteoporosis”.

Insulin

Many patients with T2DM ultimately require therapy withinsulin to achieve adequate glycemic control. Insulin stimu-lates proliferation, differentiation and survival of osteoblastsin vitro [4] and increases bone formation in a rodentmodel [5].In clinical studies, circulating insulin levels are positivelyassociated with BMD in diabetic and non-diabetic populations[6, 7]. Studies evaluating the effects of insulin therapy onfracture risk are only observational. Several identify insulintreatment to be associated with increased fracture risk [8–10].It is unlikely that insulin directly increases skeletal fragilityand more likely that the relationship between insulin therapyand fracture risk is mediated by the increased risk of falls,diabetes duration and diabetes complications in insulin-treatedpatients [10]. Recent evidence from RCTs suggests that inten-sive glycemic control in T2DM produces few benefits andimportant harms [11, 12]. Adjusting glycemia targets in re-sponse to this evidence should reduce the risk of falls relatedto insulin-induced hypoglycemia.

Sulfonylureas

These agents are insulin secretagogues, so could theoreticallyimprove bone health because insulin might increase boneformation. Data on their skeletal effects are very limited, even

This article is part of the Topical Collection on Bone and Diabetes

A. Grey (*)Department of Medicine, University of Auckland, Private Bag92019, Auckland, New Zealande-mail: a.grey@auckland.ac.nz

Curr Osteoporos Rep (2015) 13:35–40DOI 10.1007/s11914-014-0250-z

in the preclinical literature. Glimiperide was reported to atten-uate bone loss in ovariectomized rats [13]. A registry-basedcase-control study reported a lower risk of hip fracture, but notof other fractures, among users of sulfonylureas than non-users [14]. Other observational data reported neutral effectsof sulfonylureas on fracture risk [15]. Sulfonylureas have beenthe active comparators in some randomized trials of morerecently developed diabetes treatments. The absence of aplacebo group renders interpretation of results in the sulfonyl-urea group difficult. However in ADOPT, a 4-year random-ized comparison of rosiglitazone, metformin and glyburide,markers of bone turnover after 1 year were within 5 % ofbaseline values in the sulfonylurea group [16]. Fracture riskduring this trial was similar in the sulfonylurea and metformingroups (1.15 and 1.2/100 patient-years, respectively) [17]. In arandomized comparison of glimiperide with pioglitazone, noinvestigator-reported fractures were recorded in the sulfonyl-urea group [18]. Collectively, these data, limited though theyare, suggest that sulfonylureas are unlikely to exert clinicallyimportant effects on bone health.

Thiazolidinediones

Thiazolidinediones (TZDs) are insulin-sensitizing drugs thatact by activating the peroxisome proliferator-activated recep-tor gamma (PPARγ) nuclear transcription factor. Two agents,pioglitazone and rosiglitazone, are used in clinical practice.PPARγ regulates the fate of mesenchymal stem cells, specif-ically their differentiation into osteoblasts or adipocytes, suchthat activation (as by TZDs) favours adipogenesis [19]. Ad-verse skeletal effects of TZDs were reported in preclinicalstudies well in advance of their approval for use in T2DM[20]. Despite a growing body of preclinical evidence of skel-etal harm from TZDs, indicating that the drugs decreasedBMD, decreased bone formation and/or increased bone re-sorption [21], no evaluation of bone end points was undertak-en in clinical trials prior to, or for several years after, TZDswere registered for clinical use. Eventually, data from obser-vational studies and small, short-term randomized clinicaltrials were found to signal skeletal harm, by demonstratingreductions in biochemical markers of bone formation andaccelerated bone loss [22–24]. Interrogation of adverse eventsdata from TZD randomized trials demonstrated an increase infracture risk (odds ratio 1.45) in patients with T2DM exposedto TZDs for 1–4 years, in comparison to those treated withmetformin or sulfonylureas [25, 26]. Time course analysessuggested the increased risk in those allocated to TZDs be-came apparent during the second year of treatment [17]. In theadverse events analyses, the increased risk was confined towomen (odds ratio 2.2 vs 1.0 in men) and to fractures in theperipheral skeleton. However, the randomized trials wereconducted in middle-aged populations, in which hip and

vertebral fractures were uncommon. Subsequently, analysesof non-randomized (observational) studies of older adultssuggested that fracture risk might also be elevated in menand in the axial skeleton [15, 27]. No clear differences infracture risk are apparent between rosiglitazone and pioglita-zone [28•], but direct comparisons have not been undertaken.

These findings prompted studies aimed at defining themagnitude, mechanism and reversibility of the TZD skeletaleffect. Recently, several RCTs have reported the effects ofTZDs on surrogate outcomes for bone health, such as BMDand bone turnover markers [29, 30•, 31•, 32•]. Intriguingly,these trials suggest that each TZD causes quite small decreases(1–2 %, compared to placebo) in BMD over 12–18 months ofuse. There was not a consistent pattern of changes in markersof bone turnover. Changes in BMD tended to be slightlygreater in trials of rosiglitazone than those of pioglitazonebut definitive conclusions are not possible in the absence ofrandomized comparisons. In the two trials which reportedBMD data during 6 months off treatment, the small detrimen-tal effects of the TZDs persisted [30•, 31•]. Thus, the mecha-nism by which TZDs increase skeletal fragility remains un-clear—the timing and magnitude of the increase in fracturerisk do not align with the small changes in surrogate markersof bone health. A question yet to be answered is whether TZDtreatment preferentially affects bone structure or quality in theappendicular skeleton. Measurements of BMD by dual-energyX-ray absorptiometry haven’t revealed accelerated lossat non-axial skeletal sites during TZD therapy [29, 31•, 32•].Data from studies of cortical bone structure are very limited; ina post hoc analysis from a subset of participants in a random-ized trial of intensive glucose-lowering therapy, inconsistenteffects of TZDs were reported on indices of cortical bonestructure [33].

Nonetheless, rigorous evidence exists that TZDs increasefracture risk in the appendicular skeleton in older women; lessrigorous evidence suggests that fracture risk in the axial skel-eton and in older men might be increased by TZD therapy.Since people with T2DM might be at increased fracture riskbecause of their disease, consideration of skeletal health andestimation of fracture risk is reasonable in older adults forwhom TZD therapy is being considered, particularly women.Alternative treatments should be prescribed to patients whoare estimated to be at high baseline fracture risk.

Metformin

Metformin is very commonly prescribed as an insulin-sensitizing agent in T2DM. It acts, at least in part, by activat-ing AMP kinase, an enzyme that is expressed in bone cells.Preclinical studies of the skeletal effects of metformin areinconsistent. Some report that metformin increases expressionof osteogenic genes in vitro and in vivo and improves BMD

36 Curr Osteoporos Rep (2015) 13:35–40

and/or bone microarchitecture in both diabetic and non-diabetic animal models [34–37]. Others suggest the druginhibits osteoblast differentiation [38, 39] and has no effecton bone structure or fracture healing [40].

Clinical studies of metformin with bone end points are few.Those that are available are active comparator trials or obser-vational studies, making interpretation difficult. With the ca-veat that a placebo-treated control group is not available, boneturnover markers decline from baseline during 6–18 monthsof metformin therapy. Greater and more consistent declinesare apparent in bone formation (13–27 %) than bone resorp-tion markers (2–19 %) [16, 29, 30•, 41]. The time course ofthe changes has not been evaluated. Nonetheless, these datapredict that bone loss might accelerate during metformintherapy. The existing BMD data are inconclusive, however.During 18 months of metformin therapy in middle-agedadults with T2DM, Borges at el. observed changes inBMD in the axial skeleton (−2.2 % at the spine, −1.5 %at the total hip) that suggested an increased rate of loss[29], but Bilizekian et al. reported stable values at the samesites (+0.04 and −0.72 % at spine and total hip, respective-ly) over 12 months [30•]. The only BMD data from theappendicular skeleton suggest stability over 18 months ofmetformin therapy [29]. Two case-control studies reportedfracture outcomes in users of metformin [8, 14]. Eachreported odds ratios below 1 for any fracture and forspecific fracture types. Such analyses have many limita-tions, but perhaps suggest it is unlikely that metformin useincreases fracture risk. Randomized comparisons of metfor-min with rosiglitazone in T2DM demonstrate lower fracturerates in women allocated to metformin [26, 42]. Ideally, arandomized controlled trial of metformin with skeletal end-points would be undertaken to clarify the issue, but giventhat such a trial is unlikely to be undertaken, the availableevidence doesn’t warrant specific focus on skeletal healthin people with T2DM taking metformin.

GLP-1 Receptor Agonists and Dipeptidyl Peptidase IVInhibitors

The incretins glucagon-like peptide 1 (GLP-1) and gastricinhibitory polypeptide (GIP) modulate glycemia by regulatingglucose-dependent insulin release. Each peptide is catabolizedby the enzyme dipeptidyl peptidase IV (DPP IV). Agents thatactivate the GLP-1 receptor or inhibit DPP IV improve glyce-mic control in T2DM. It is plausible that such drugs alsoimprove bone health. Thus, deletion of the GLP-1 receptorin mice increases bone resorption and decreases cortical bonedensity [43], and GIP overexpression increases bone forma-tion and bone density [44]. Other preclinical evidence sug-gests that GLP-1 receptor agonism increases bone formation,decreases bone resorption and increases BMD [45, 46]. Sev-eral GLP-1 agonists are in clinical use for T2DM. Very fewdata are available on their skeletal effects in humans. In asmall, 1-year randomized active comparator trial, exenatidedid not affect markers of bone turnover or total body BMDcompared to insulin glargine [47].

Two recent meta-analyses of fractures reported in random-ized trials of GLP-1 receptor agonists emphasized the lack ofavailable data, being based on 19 and 48 fractures, respective-ly [48, 49].

Dipeptidyl peptidase IV (DPP IV) inhibitors, several ofwhich are in clinical use, increase levels of GLP-1 and GIP,and might therefore influence bone metabolism. Preclinicalstudies reported mixed results. Ablation of DPP IVexpressionin mice did not produce a bone phenotype [50]. Sitagliptin didnot alter BMD or bone histomorphometry in ovariectomizedrats [51], and another DPP IV inhibitor did not change bonemetabolism or structure in mice [52]. While sitagliptin im-proved trabecular bone structure and bone strength in diabeticrats [53], saxagliptin was reported to reduce osteoblast differ-entiation and proliferation in vitro and reduce osteoblast num-ber in vivo in non-diabetic rats [54]. In humans, a small 1-year

Table 1 Summary of results of clinical studies of effects of diabetes treatments on skeletal outcomes

Bone turnover markers Bone mineral density Fracture risk

Sulphonylureas ND ND ↔ (a)

Metformin ↓ (a) ↓/↔ (a) ↔ (b)

Thiazolidinediones ↓/↔ formation (c); ↑/↔ resorption (c) ↓/↔ (c) ↑ (c)i

GLP-1 receptor agonists ↔ (c)ii ↔ (c)ii ID

DPP IV inhibitors ↔ (c)ii ID ↔ (c)

Renal sodium-glucose transport inhibitors ↔ (c) ↔ (c) ↑ (c)ii

Insulin ND ↑ (a) ↑ (a)

Letters in parenthesis indicate the highest level of evidence available, (a) prospective cohort studies, (b) case-control studies, (c) randomized controlledtrials

ND no data, ID insufficient data, GLP glucagon like peptide, DPP dipeptidyl peptidase, ↔ unchangedi In appendicular skeleton in womenii Data limited to one small trial

Curr Osteoporos Rep (2015) 13:35–40 37

RCT in people with T2DM did not find any effect ofvildagliptin on markers of bone turnover, but interpretationis limited by postprandial measurement of the food-sensitiveresorption marker [55]. In a short-term (12 week) evaluation,sitagliptin reduced markers of bone turnover by 10–35% [56].Although a meta-analysis of small RCTs of short durationreported a reduced risk of fractures during treatment withDPP IV inhibitors [57], a large (>16,000 participants) 2-yearRCT with primary cardiovascular end points reported nodifference in fracture incidence between participants treatedwith saxagliptin or placebo [58]. On the basis of the availableevidence, it seems unlikely that this class of drugs importantlyaffects bone health.

Sodium-Glucose Co-transporter 2 Inhibitors

This relatively new class of drugs improves glycemic controlby promoting renal glucose excretion. A 12-month placebo-controlled randomized trial of the first agent from this class ofdrugs, dapagliflozin, in postmenopausal women with T2DMfound no effect of the drug on either markers of bone turnoveror BMD in the axial skeleton [59]. During a total of 2 years ofobservation, one fracture occurred in each treatment group[60]. However, a larger and longer (2 years) RCT in peoplewith T2DM and moderate renal impairment found significant-ly more fractures in the participants exposed to dapagliflozin[61]. Although the number of fractures (13) was small, they alloccurred in participants exposed to the sodium-glucose co-transporter 2 (SGLT2) inhibitor. It remains to be determinedwhether this observation is robust, but it requires carefulevaluation in future studies. In light of the experience withTZDs, where surrogate markers of bone health did not alignneatly with fracture outcomes, data on BMD and/or boneturnover end points should not be relied upon to preciselypredict the most important outcome, fracture, in T2DM.

Summary

The impact of treatments for T2DM on bone health is impor-tant, given the likelihood that the disease causes a modestlyincreased risk of fracture. However, the quality of evidenceavailable to evaluate this issue is low (Table 1). To somedegree, this reflects the paucity of large, placebo-controlledRCTs with hard clinical end points in T2DM. It also reflectsthe relatively recent recognition of fracture as an outcome ofinterest in the disease. Inconsistency exists for some agentsbetween the findings in preclinical studies and those in clinicalstudies. With all of those caveats, good evidence exists forskeletal harm caused by TZDs, and those drugs should beavoided in the management of patients with moderate or highbaseline fracture risk. Avoiding overtreatment with

medications that cause hypoglycemia, such as insulin andsulfonylureas, is recommended to reduce the risk ofhypoglycaemia-induced falls. For the other agents currentlyin use, the available evidence does not suggest importanteffects on bone health.

Compliance with Ethics Guidelines

Conflict of Interest A. Grey declares no conflicts of interest.

Human and Animal Rights and Informed Consent All studies by A.Grey involving animal and/or human subjects were performed afterapproval by the appropriate institutional review boards. When required,written informed consent was obtained from all participants.

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