Pamidronate Attenuates Muscle Loss After Pediatric Burn Injury

Children who are burned >40% total body surface area lose significant quantities of both bone and muscle mass because of acute bone resorption, inflammation, and endogenous glucocorticoid production, which result in negative nitrogen balance. Because administration of the bisphosphonate pamidronate within 10 days of the burn injury completely prevents the bone loss, we asked whether muscle protein balance was altered by the preservation of bone. We reviewed the results from 17 burned pediatric subjects previously enrolled in a double‐blind randomized controlled study of pamidronate in the prevention of post‐burn bone loss and who were concurrently evaluated for muscle protein synthesis and breakdown by stable isotope infusion studies during the acute hospitalization. We found a significantly lower fractional protein synthesis rate (FSR) in the pamidronate group and a correspondingly lower rate of appearance of the amino acid tracer in venous blood, suggesting lower muscle protein turnover. Moreover, net protein balance (synthesis minus breakdown) was positive in the subjects receiving pamidronate and negative in those receiving placebo. Muscle fiber diameter was significantly greater in the pamidronate subjects and leg strength at 9 months post‐burn was not different between subjects who received pamidronate and normal physically fit age‐matched children studied in our lab. Leg strength in burned subjects who served as controls tended to be weaker, although not significantly so. If substantiated by a larger study, these results suggest that bone may have a paracrine mechanism to preserve muscle and this finding may have implications for the treatment of sarcopenia in the elderly. © 2014 American Society for Bone and Mineral Research.

[1]  Yusu Gu,et al.  Impaired exercise capacity and skeletal muscle function in a mouse model of pulmonary inflammation. , 2013, Journal of applied physiology.

[2]  L. Formigli,et al.  Bone Marrow Mesenchymal Stromal Cells Stimulate Skeletal Myoblast Proliferation through the Paracrine Release of VEGF , 2012, PloS one.

[3]  D. Herndon,et al.  The Effect of Ketoconazole on Post-Burn Inflammation, Hypermetabolism and Clinical Outcomes , 2012, PLoS ONE.

[4]  B. Olwin,et al.  Growth of limb muscle is dependent on skeletal-derived Indian hedgehog. , 2011, Developmental biology.

[5]  R. Weinstein,et al.  Connexin 43 Is Required for the Anti‐Apoptotic Effect of Bisphosphonates on Osteocytes and Osteoblasts In Vivo , 2008, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[6]  Xiaoping Zhou,et al.  The Proinflammatory Cytokine, Interleukin-6, Up-regulates Calcium-sensing Receptor Gene Transcription via Stat1/3 and Sp1/3* , 2008, Journal of Biological Chemistry.

[7]  N. Watts,et al.  Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy , 2008, Osteoporosis International.

[8]  D. Chinkes,et al.  Pamidronate preserves bone mass for at least 2 years following acute administration for pediatric burn injury. , 2007, Bone.

[9]  D. Herndon,et al.  The efficacy of acute administration of pamidronate on the conservation of bone mass following severe burn injury in children: a double-blind, randomized, controlled study , 2005, Osteoporosis International.

[10]  D. Herndon,et al.  Evidence supporting a role of glucocorticoids in short-term bone loss in burned children , 2004, Osteoporosis International.

[11]  T. Rosol,et al.  Parathyroid hormone (PTH) secretion, PTH mRNA and calcium-sensing receptor mRNA expression in equine parathyroid cells, and effects of interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha on equine parathyroid cell function. , 2003, Journal of molecular endocrinology.

[12]  D. Herndon,et al.  Effects of a 12-wk resistance exercise program on skeletal muscle strength in children with burn injuries. , 2001, Journal of applied physiology.

[13]  E. Brown,et al.  Up-regulation of the parathyroid calcium-sensing receptor after burn injury in sheep: A potential contributory factor to postburn hypocalcemia , 2000, Critical care medicine.

[14]  D. Chinkes,et al.  Determinants of Skeletal Muscle Catabolism After Severe Burn , 2000, Annals of surgery.

[15]  D. Chinkes,et al.  Persistence of muscle catabolism after severe burn. , 2000, Surgery.

[16]  E. Brown,et al.  Inhibition of PTH secretion by interleukin-1 beta in bovine parathyroid glands in vitro is associated with an up-regulation of the calcium-sensing receptor mRNA. , 1997, Biochemical and biophysical research communications.

[17]  R. Eastell,et al.  Histomorphometric and biochemical characterization of bone following acute severe burns in children. , 1995, Bone.