Biomechanical effects of recombinant human growth hormone on bones and muscles of ovariectomized rats

GUSTAVO ROBERTO COINTRY; JOSÉ LUIS FERRETTI; RICARDO FRANCISCO CAPOZZA; PAOLA REINA; NÉSTOR MATÍAS FRACALOSSI; SARA FELDMAN

Río de Janeiro (Brasil)

Congreso; IOF World Congress on Osteoporosis; 2004

International Osteoporosis Foundation

AIM AND METHODS    The mechanical properties of bones ( stiffness and strength of whole bones ) are determined by the stiffness and the stress-supporting ability of the mineralized tissue ( bone material´s properties ) and the spatial distribution of that tissue ( geometric properties;).     A biomechanical feedback system called  "mechanostat" controls bone deformability by sensing the strains provoked in every skeletal region by customary mechanical usage and orienting directionally bone modeling and remodeling accordingly. As a result, bones maintain the usage-derived strains ( chiefly determined by the regional muscle contractions ) far away from the critical strain levels at which a fracture occurs.     Estrogens are known to inhibit periosteal growth and endosteal remodeling, and growth hormone ( GH ) is known to stimulate periosteal growth and muscle development. Effects of these hormones may alter the biomechanical setpoints of the bone mechanostat (critical values of bone strain) for triggering bone modeling and disuse-mode remodeling.     In order to analyze the separate and combined effects of ovariectomy (OX) and exogenous GH on cortical bone properties and on bone structure and on the muscle-bone interactions, doses of 150 IU/kg/d of rhGH were given during 3 months to 3-month old rats, either intact (GH group) or OX (OX+GH group) rats. Both intact and OX controls were also studied (C and OX groups). At the end of the study their femur diaphyses were scanned by pQCT at the midpoint and tested in bending. The gastrocnemius muscles were weighed in fresh condition.  RESULTS    OX reduced bone tissue´s mineralization and stiffness.     A significant enhancement of bone growth in width improved significantly the cross-sectional architecture of the diaphyses (polar moment of inertia, pCSMI).     This geometric improvement overcompensated the negative impact of the OX-induced impairment on bone material´s mineralization and stiffness, thus the diaphyseal strength was increased. The assayed dose of rhGH was little effective in intact rats. However, it prevented the OX-induced impairment in bone tissue´s mineralization (not stiffness) and improved additively the OX-enhanced geometric variables. These effects of OX and rhGH were correlative with additive increases in muscle mass. Simple regression analyses showed that the impact of the muscular improvement was more evident on bone architecture than it was on bone strength.     The positive OX and rhGH effects on cortical bone mass and architecture seemed to have derived from the induction of an "anabolic" shift of the bone mechanostat threshold for triggering bone modeling during growth, with a positive biomechanical impact on the diaphyses (larger CSMI and fracture load than controls). The apparent incongruence between the repercussion of the additive improvement in muscle mass induced by OX and rhGH on bone geometry (large impact) and strength (relatively low impact) can be explained by the impairment in bone material´s stiffness induced by OX and not prevented by rhGH (perhaps because rhGH did not act on the microstructure of the mineralized tissue). Based on original arguments, these evidences support the possible ability of rhGH to improve human post-menopausal osteopenias with a relatively large impairment in cortical bone mass and / or distribution. However, the actual benefit of the positive rhGH effects on bone mass and architecture in any species would remain uncertain as long as the nature of rhGH effects on the OX-impaired bone´s material stiffness is unknown. In addition, these results are interesting because they defy the prevailing view that the remaining bone tissue in metabolic osteopenias is normal. Conclusions 1. rhGH protected and improved bone geometric properties in OX rats, but the biomechanical impact of this effect was lower than expected. 2. The reason may be that rhGH failed to prevent the OX-induced impairment of bone material properties, despite to protect bone tissue mineralization. 3. Data suggests that the OX-induced impairment of bone material would involve some microstructural components of bone matrix; this would defy the prevailing hypothesis that in metabolic osteopenias the remaining bone is qualitatively normal.