Effect of pioglitazone on bone mineral density in patients with nonalcoholic steatohepatitis: A 36‐month clinical trial

Background The effects of pioglitazone on bone metabolism are unclear. This study evaluated the long‐term effects of pioglitazone on bone mineral density (BMD) and bone metabolism in patients with prediabetes or type 2 diabetes mellitus (T2DM) and non‐alcoholic steatohepatitis (NASH). Methods Ninety‐two patients with prediabetes or T2DM and biopsy‐proven NASH with BMD and baseline biochemical bone measurements were included. Patients (mean [±SEM] age 51 ± 1 years, 71% male, mean body mass index 34.5 ± 0.5 kg/m2) were randomly assigned to pioglitazone (45 mg/day) or placebo for 18 months, followed by an 18‐month open‐label pioglitazone treatment phase. Baseline, 18‐ and 36‐month evaluations included plasma vitamin D and bone turnover biomarker levels, and BMD measurements at the spine, femoral neck, total hip, and one‐third radius. Results After 18 months of pioglitazone treatment, there were no differences in BMD versus placebo at either the femoral neck (P =0.87), total hip (P =0.78), or one‐third radius (P =0.44); however, bone density decreased at the level of the spine with pioglitazone (−3.5%; P =0.002). During the extension phase (18–36 months), patients had no further decreases in BMD or plasma biomarkers of bone turnover during pioglitazone treatment. No patient experienced a low‐energy bone fracture. Conclusions Treatment of patients with prediabetes or T2DM with pioglitazone for up to 3 years was associated with decreased BMD at the level of the lumbar spine. This reduction in BMD at the lumbar spine at 18 months versus placebo suggests an early deleterious effect of pioglitazone on bone metabolism. 摘要 背景 吡格列酮对骨代谢的影响目前尚未明确。这项研究在合并糖尿病前期或2型糖尿病(T2DM)的非酒精性脂肪性肝炎(non‐alcoholic steatohepatitis，NASH)患者中评估了吡格列酮对骨密度(bone mineral density，BMD)以及骨代谢的长期影响。 方法纳入了92名糖尿病前期或者T2DM患者，他们经肝穿活检证实为NASH，测定了他们的BMD以及基线时的骨代谢指标。患者(平均年龄[±SEM]为51 ± 1岁，71%为男性，平均体重指数为34.5 ± 0.5 kg/m2)，患者被随机分配到吡格列酮(45 mg/d)组或者安慰剂组，共治疗18个月，接着又使用开放标签的吡格列酮继续治疗18个月。在基线、第18个月以及第36个月时评估的指标如下:血浆维生素D与骨转换生物标记物水平以及椎骨、股骨颈、全髋与桡骨前三分之一的BMD测量值。 结果 吡格列酮治疗18个月后，治疗组的股骨颈(P = 0.87)、全髋(P = 0.78)或者桡骨前三分之一(P =0.44)的BMD与安慰剂组相比都没有差异；然而，吡格列酮治疗组椎骨水平的骨密度却有所下降(‐3.5%；P = 0.002)。在扩展期(第18‐36个月时)，吡格列酮治疗组患者的BMD没有进一步下降，血浆骨转换生物标记物水平也没有下降。没有患者发生低能量骨折(即由于骨质疏松症，例如站立或坐下后跌倒的骨折)。 结论 糖尿病前期或T2DM患者使用吡格列酮治疗长达3年后会降低腰椎BMD。第18个月时治疗组的腰椎BMD与安慰剂组相比出现了下降，这提示吡格列酮对骨代谢具有早期的有害影响。 Highlights Treatment with pioglitazone was associated with a significant reduction in spine bone mineral density (BMD) in a cohort of patients predominantly composed of male i