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Thiazolidinediones: New Evidence of Bone Loss Editorial
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The Journal of Clinical Endocrinology & Metabolism April 2007
Vol. 92, No. 4 1232-1234
Ann V. Schwartz and Deborah E. Sellmeyer
Department of Epidemiology and Biostatistics (A.V.S.) and Division of Endocrinology and Metabolism Department of Medicine (D.E.S.) University of California, San Francisco San Francisco, California 94107
The thiazolidinediones (TZDs) improve insulin sensitivity and are widely prescribed for treatment of type 2 diabetes. Rosiglitazone and pioglitazone, the two TZDs currently approved for clinical use, have been available since 1999. Troglitazone became available in 1997 but was withdrawn in 2000 due to rare cases of liver toxicity. The TZDs have been extensively studied as a treatment for diabetes and have been shown to reduce progression to diabetes in those with impaired glucose metabolism. Although animal models and observational data in humans indicate that TZDs may cause reduced bone formation and bone loss (1, 2), little is known about the clinical effects of these hypoglycemic medications on the skeleton. In this issue, Grey et al. (3) provide the first evidence from a randomized trial that rosiglitazone causes bone loss. The trial enrolled healthy postmenopausal women who did not have diabetes or osteoporosis. After 14 wk of treatment with rosiglitazone, participants experienced a significant decrease in bone density (-1.9% rosiglitazone vs. -0.2% placebo) at the total hip accompanied by a modest reduction (-8 to -13%) in bone formation markers without a change in resorption markers.
The findings from this trial are particularly compelling given the recent ADOPT (A Diabetes Outcome Progression Trial) results, showing a higher risk of fractures in diabetic women, but not men, on rosiglitazone monotherapy compared with metformin or glyburide (4). The ADOPT trial enrolled 4360 participants, including 1849 women, with a mean age of 57 yr and followed them for a median of 4 yr. The main outcome was time to monotherapy failure based on fasting glucose. Fractures were not a specified outcome of the trial but were identified through adverse event reports. The proportion of women reporting any fracture was 9.3% for rosiglitazone, 5.1% for metformin, and 3.5% for glyburide. The increased risk was evident for lower limb and upper limb fractures. Only four women experienced a hip fracture, and the proportion did not differ by treatment. For men, the proportion experiencing a fracture was similar across treatments (rosiglitazone 3.9%, metformin 3.4%, and glyburide 3.3%).
Although the trial by Grey et al. was conducted among nondiabetic women, it seems likely that these results apply to diabetic women as well, given the increased fracture rates seen in the ADOPT trial. In addition, we have previously reported increased bone loss in diabetic women, but not men, taking any TZD (rosiglitazone, pioglitazone, and troglitazone combined) in the Health, Aging and Body Composition (Health ABC) observational study (2).
Type 2 diabetes itself appears to be a risk factor for fracture in older adults, based on studies that were largely conducted before TZDs were available (5). Thus, treatment with rosiglitazone may be adding to an already increased burden of fracture among older diabetic adults.
In rodent models, rosiglitazone treatment decreases osteoblast function and increases bone loss (6, 7, 8). Rosiglitazone is known to activate the nuclear hormone receptor peroxisome proliferator-activated receptor-y (PPAR-y), resulting in improved insulin sensitivity. In addition to this antidiabetic effect, PPAR- activation influences the lineage allocation of mesenchymal stem cells (MSC) in the bone marrow. Rosiglitazone increases the allocation of MSC toward adipocytes and decreases differentiation toward osteoblasts. The effect of PPAR-y activation on osteoclasts is not as clearly established. Some animal models have found no effect on osteoclasts (6, 7, 8), but others have found increased bone resorption (9). In addition to bone loss, rosiglitazone treatment results in greater marrow adiposity in animal models (6, 9).
Because rosiglitazone may increase marrow fat, the extent of bone loss with treatment may not be accurately assessed using dual energy x-ray absorptiometry (DXA). DXA scans [and standard single energy quantitative computed tomography (QCT) scans] are susceptible to artificial decreases in bone mineral density (BMD) with increased marrow fat. The extent of this effect has been tested in phantom and cadaver models but is difficult to assess in vivo (10, 11). Clinical studies are needed to ascertain whether rosiglitazone is causing substantial changes in bone marrow fat to further test the hypothesis that rosiglitazone is affecting bone through changes in MSC lineage allocation. And, if marrow fat is increased, other methods of measuring changes in bone, such as high-resolution peripheral QCT, are needed to accurately assess bone loss. QCT would also identify changes in volumetric bone density with separate assessments of trabecular and cortical bone, potentially illuminating the mechanism of TZDs' action on bone.
The study in this issue of the journal (3) investigated 14 wk of rosiglitazone therapy in postmenopausal women and found 1.7% more bone loss in the treated group compared with placebo. Whether this rate of bone loss continues or bone density stabilizes or even recovers is not known. If the rate of bone loss identified in this trial continued for a year, the additional loss with rosiglitazone therapy would be 6.8%, compared with an average loss in postmenopausal women of about 1% annually. However, in the Health ABC study, additional annual bone loss in older diabetic women using any TZD was lower: 0.5% at the total hip and 1.2% at the spine (2). These differences might be due to the longer follow-up time in Health ABC, the older average age of participants (73 yr), or combining three TZDs. Although the combined evidence from bone markers, DXA scans, and fracture risk clearly suggests that rosiglitazone is causing clinically important bone loss, at least in postmenopausal women, the degree of bone loss remains a question. Longer-term studies are needed, possibly using methods other than DXA, to clarify the extent of bone loss.
Rosiglitazone may not have negative skeletal effects in all patients. Results from Health ABC and ADOPT suggest that bone loss and fracture risk may not be increased in men. The pathophysiology underlying this apparent difference is not clear. In one animal model, ovariectomized, but not intact, rats experienced bone loss with rosiglitazone treatment (9). Further research is needed to determine whether rosiglitazone causes bone loss in men and premenopausal women.
Takeda recently reported in a letter to healthcare providers that pioglitazone also appears to increase fracture risk in women, but not men. In their clinical trial database, the incidence of fractures reported as adverse events among women was 1.9 vs. 1.1 per 100 patient-years for pioglitazone vs. a comparator (either placebo or active). Rodent models have reported increased bone loss (12, 13), and an in vitro model has demonstrated antiosteoblastic and proadipocytic effects (1). Although these data suggest a negative effect of pioglitazone on bone, this needs to be tested further in clinical trials. In contrast, investigations of troglitazone found increased marrow fat without bone loss in a mouse model (14), although in vitro models show antiosteoblastic effects (1). One small clinical study of troglitazone found no change in spine T-score after 12 months of treatment (15). Other evidence indicates that PPAR- antiosteoblastic activities might be separated from its antidiabetic activities by using TZDs with different chemical structures (16). In a mouse model, netoglitazone, an experimental TZD, induced marrow adipocyte formation but did not cause bone loss (17).
The demonstrated clinical effects of rosiglitazone on the skeleton provide insight for research into the mechanisms underlying age-related bone loss. Marrow adiposity increases with age while BMD declines, supporting the hypothesis that reduced osteoblastogenesis with increased adipogenesis of MSC is an important pathway for age-related bone loss. The bone loss demonstrated with rosiglitazone activation of PPAR- provides support for the hypothesis that this pathway plays a role in the development of osteoporosis.
A clearer understanding of the mechanisms underlying the skeletal effects of TZDs will advance our knowledge of osteoporosis. Activation of PPAR- might affect bone negatively through several pathways. Suppression of genes for osteoblast differentiation has been demonstrated (6). Suppression of the Wnt signaling pathway (18) and down-regulation of IGF-I could also be contributing factors (19). There may be an increased apoptosis of mature osteoblasts in addition to a reduction in osteoblast differentiation. The bone marker results reported by Grey et al. suggest that rosiglitazone affects bone formation but not resorption in humans. Further investigation of the degree of imbalance between formation and resorption is needed.
In sum, the new evidence that rosiglitazone has negative effects on skeletal health should be followed up with human and animal studies that can delineate the risks and mechanisms of TZDs action on bone. Larger randomized clinical trials are needed to identify the longer-term effects on bone density, including volumetric BMD, to obtain measures of marrow fat, to clarify the accuracy of DXA measurements in the context of TZD therapy, and to ascertain the groups that are at risk. Research using animal and in vitro models is needed to probe the mechanisms underlying the effect of TZDs on bone and to test preventive treatments such as bisphosphonates and PTH.
Although there is more work to be done, health care providers need to be aware of the possibility of increased bone loss and fracture risk associated with TZD use. At this time, it would seem prudent to consider a patient's risk factors for fracture when prescribing TZD therapy. The data to date are most consistent for adverse skeletal effects in middle-aged and older women. Current published guidelines for the age at which osteoporosis screening in postmenopausal women should begin vary from the time of menopause to age 65 yr. For postmenopausal women with diabetes, particularly those on TZD therapy, it would seem reasonable to begin screening earlier rather than later. Osteoporosis therapy should be initiated in those women whose bone density and other risk factors place them at an increased risk for fracture. For older men, osteoporosis screening is indicated for those with a medical condition or medication that may cause bone loss. There is currently insufficient evidence to advocate routine osteoporosis screening for all older men on TZD therapy. However, fracture risk and the need for bone density testing should already be considered for all older men. The presence of diabetes and, in particular, TZD therapy should lower the threshold for obtaining a bone density test in an older man. In younger individuals, absolute fracture rates are very low, and the value of bone density testing has not been established. Younger individuals should be selected for bone density testing on an individual basis, considering their overall clinical scenario with the presence of diabetes and TZD therapy incorporated. All patients should optimize nutrition and lifestyle factors that can protect skeletal health; these recommendations are very consistent with those for type 2 diabetes. In patients with diabetes on TZD therapy, particularly older individuals, having a lower threshold for obtaining bone density testing would seem appropriate as we await more definitive data. Additional research is needed to ascertain the degree of bone loss and fracture risk in postmenopausal women associated with longer term TZD therapy and to identify whether TZDs have negative skeletal effects in men and premenopausal women. Given the known benefits of TZD therapy for diabetes, the benefits of therapy may still outweigh the side effects, particularly in those with a low risk of fracture.
Footnotes
Abbreviations: BMD, Bone mineral density; DXA, dual energy x-ray absorptiometry; MSC, mesenchymal stem cells; PPAR-, peroxisome proliferator-activated receptor-; TZD, thiazolidinedione; QCT, quantitative computed tomography.
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