title: Theophylline, a methylxanthine drug induces osteopenia and alters calciotropic hormones, and prophylactic vitamin D treatment protects against these changes in rats.
abstract: The drug, theophylline is frequently used as an additive to medications for people suffering from chronic obstructive pulmonary diseases (COPD). We studied the effect of theophylline in bone cells, skeleton and parameters related to systemic calcium homeostasis. Theophylline induced osteoblast apoptosis by increasing reactive oxygen species production that was caused by increased cAMP production. Bone marrow levels of theophylline were higher than its serum levels, indicating skeletal accumulation of this drug. When adult Sprague-Dawley rats were treated with theophylline, bone regeneration at fracture site was diminished compared with control. Theophylline treatment resulted in a time-dependent (at 4- and 8 weeks) bone loss. At 8 weeks, a significant loss of bone mass and deterioration of microarchitecture occurred and the severity was comparable to methylprednisone. Theophylline caused formation of hypomineralized osteoid and increased osteoclast number and surface. Serum bone resorption and formation marker were respectively higher and lower in the theophylline group compared with control. Bone strength was reduced by theophylline treatment. After 8 weeks, serum 25-D3 and liver 25-hydroxylases were decreased in theophylline group than control. Further, theophylline treatment reduced serum 1, 25-(OH)2 vitamin D3 (1,25-D3), and increased parathyroid hormone and fibroblast growth factor-23. Theophylline treated rats had normal serum calcium and phosphate but displayed calciuria and phosphaturia. Co-administration of 25-D3 with theophylline completely abrogated theophylline-induced osteopenia and alterations in calcium homeostasis. In addition, 1,25-D3 protected osteoblasts from theophylline-induced apoptosis and the attendant oxidative stress. We conclude that theophylline has detrimental effects in bone and prophylactic vitamin D supplementation to subjects taking theophylline could be osteoprotective.
authors: Division of Endocrinology and Center for Research in Anabolic Skeletal Target in Health and Illness (ASTHI), Central Drug Research Institute (CDRI), Council of Scientific and Industrial Research (CSIR), Lucknow 226021, India.
authors: Subhashis
authors: S
authors: Pal
authors: Division of Endocrinology and Center for Research in Anabolic Skeletal Target in Health and Illness (ASTHI), Central Drug Research Institute (CDRI), Council of Scientific and Industrial Research (CSIR), Lucknow 226021, India.
authors: Kainat
authors: K
authors: Khan
authors: Division of Endocrinology and Center for Research in Anabolic Skeletal Target in Health and Illness (ASTHI), Central Drug Research Institute (CDRI), Council of Scientific and Industrial Research (CSIR), Lucknow 226021, India.
authors: Shyamsundar Pal
authors: SP
authors: China
authors: Division of Endocrinology and Center for Research in Anabolic Skeletal Target in Health and Illness (ASTHI), Central Drug Research Institute (CDRI), Council of Scientific and Industrial Research (CSIR), Lucknow 226021, India.
authors: Monika
authors: M
authors: Mittal
authors: Division of Endocrinology and Center for Research in Anabolic Skeletal Target in Health and Illness (ASTHI), Central Drug Research Institute (CDRI), Council of Scientific and Industrial Research (CSIR), Lucknow 226021, India.
authors: Konica
authors: K
authors: Porwal
authors: Division of Toxicology, CDRI-CSIR, Lucknow 226021, India.
authors: Richa
authors: R
authors: Shrivastava
authors: Pharmacokinetics and Metabolism Division, CDRI-CSIR, Lucknow 226021, India.
authors: Isha
authors: I
authors: Taneja
authors: Pharmacokinetics and Metabolism Division, CDRI-CSIR, Lucknow 226021, India.
authors: Zakir
authors: Z
authors: Hossain
authors: Division of Medicinal and Process Chemistry, CDRI-CSIR, Lucknow 226021, India.
authors: Dhanaraju
authors: D
authors: Mandalapu
authors: Pharmacokinetics and Metabolism Division, CDRI-CSIR, Lucknow 226021, India.
authors: Jiaur R
authors: JR
authors: Gayen
authors: Pharmacokinetics and Metabolism Division, CDRI-CSIR, Lucknow 226021, India.
authors: Muhammad
authors: M
authors: Wahajuddin
authors: Division of Medicinal and Process Chemistry, CDRI-CSIR, Lucknow 226021, India.
authors: Vishnu Lal
authors: VL
authors: Sharma
authors: Division of Biochemistry, CDRI-CSIR, Lucknow 226021, India.
authors: Arun K
authors: AK
authors: Trivedi
authors: Division of Biochemistry, CDRI-CSIR, Lucknow 226021, India.
authors: Sabyasachi
authors: S
authors: Sanyal
authors: Division of Toxicology, CDRI-CSIR, Lucknow 226021, India.
authors: Smrati
authors: S
authors: Bhadauria
authors: Department of Medical Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India.
authors: Madan M
authors: MM
authors: Godbole
authors: Department of Medical Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India.
authors: Sushil K
authors: SK
authors: Gupta
authors: Division of Endocrinology and Center for Research in Anabolic Skeletal Target in Health and Illness (ASTHI), Central Drug Research Institute (CDRI), Council of Scientific and Industrial Research (CSIR), Lucknow 226021, India. Electronic address: n_chattopadhyay@cdri.res.in.
authors: Naibedya
authors: N
authors: Chattopadhyay
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers; D001851:Bone Diseases, Metabolic / Q000139:chemically induced*; D001853:Bone Marrow / Q000378:metabolism; D001861:Bone Regeneration / Q000187:drug effects; D002112:Calcifediol / Q000378:metabolism; D018929:Cell Culture Techniques; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D050723:Fractures, Bone / Q000503:physiopathology; D008297:Male; D008775:Methylprednisolone / Q000494:pharmacology; D010006:Osteoblasts / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013806:Theophylline / Q000493:pharmacokinetics / Q000494:pharmacology*; D013997:Time Factors; D014807:Vitamin D / Q000494:pharmacology*
chemical_list: D015415:Biomarkers; D010281:Parathyroid Hormone; D017382:Reactive Oxygen Species; D014807:Vitamin D; D013806:Theophylline; D000242:Cyclic AMP; D002112:Calcifediol; D008775:Methylprednisolone
keywords: 25-Hydoxylase; Biomechanical strength; Fibroblast growth factor-23; Fracture healing; Micro-computed tomography; Receptor–activator of nuclear factor kappa B ligand