The Effect of Rosiglitazone on Bone Mass and Fragility Is Reversible and Can Be Attenuated With Alendronate

Abstract

Rosiglitazone (RSG) is an antidiabetic drug that has been associated with increased peripheral fractures, primarily in postmenopausal women. In this report, we investigated the underlying mechanisms of RSG-associated bone loss in ovariectomized (OVX) rats and determined whether changes in bone parameters associated with RSG administration are reversible on treatment cessation or preventable by coadministration with an antiresorptive agent. Nine-month-old Sprague-Dawley rats underwent OVX or sham operation. Sham-operated rats received oral vehicle only; OVX animals were randomized to receive vehicle, RSG, alendronate (ALN), or RSG plus ALN for 12 weeks. All treatment started the day after ovariectomy. After the 12-week treatment period, the OVX and RSG groups also underwent an 8-week treatment-free recovery period. Bone densitometry measurements, bone turnover markers, biomechanical testing, and histomorphometric analysis were conducted. Microcomputed tomography was also used to investigate changes in microarchitecture. RSG significantly increased deoxypyridinoline levels compared with OVX. Significant exacerbation of OVX-induced loss of bone mass, strength, and microarchitectural deterioration was observed in RSG-treated OVX animals compared with OVX controls. These effects were observed predominantly at sites rich in trabecular bone, with less pronounced effects in cortical bone. Coadministration of RSG and ALN prevented the bone loss associated with RSG treatment. Following cessation of RSG treatment, effects on bone mass and strength showed evidence of reversal. Thus, treatment of OVX rats with RSG results in loss of bone mass and strength, primarily at sites rich in trabecular bone, mainly due to increased bone resorption. These effects can be prevented by concomitant treatment with ALN and may be reversed following discontinuation of RSG.

The Alliance of Mesenchymal Stem Cells, Bone, and Diabetes

“…Considering that TZDs are PPAR γ agonists, a possible disruption in bone formation has been suggested. However, TZD are also known to lower RANKL activity and a recent study on ovariectomized rats indicates that bone impairment induced by rosiglitazone treatment is due to reduced bone strength coming from increased resorption mainly in sites rich in trabecular bone, which was reverted by treatment with alendronate [319]. Less evidence is available for pioglitazone.…”

Effects of TZD Use and Discontinuation on Fracture Rates in ACCORD Bone Study

“…In a rodent model (7) and a clinical trial (8), the more rapid bone loss associated with rosiglitazone use was attenuated after use was discontinued. However, the effects of discontinuation on the key outcome of fracture risk are not known.…”

All-trans retinoic acid shifts rosiglitazone-induced adipogenic differentiation to osteogenic differentiation in mouse embryonic fibroblasts

“…As the availability of potent drugs for insulin resistance remains very limited, the FDA has approved the use of RSG at the risk of potential heart toxicity. Clinically, some specific drugs are used in combination with RSG to attenuate or prevent the RSG-induced osteoporosis, such as alendronate (4), a type of bisphosphonate. Bisphosphonates show high a affinity with the bone matrix and inhibit osteoclastogenesis, which blocks the RSG-induced loss of bone mass (4).…”

“…Therefore, the balance between bone formation and bone absorption is distrupted. To date, bisphosphonates have been used together with RSG or its analogs in the treatment of type 2 diabetes mellitus for preventing osteoporosis by blocking osteoclastogenesis (4,5). Although bisphosphonates prevent the decrease in bone density, they are also associated with some serious adverse effects (6–9).…”