EDITORS: Black-and-white photos comparing magnified cross-sections of bone in experimental and control mice are available on request.

ANN ARBOR—Laboratory mice which have been genetically altered to produce human growth hormone grow to be 25-30 percent larger than normal mice—with much of that size difference coming from bigger bones, according to University of Michigan researchers. The trade-off for bigger bones in adolescence, however, appears to be poorer bone quality, increased brittleness and less resistance to fractures as mice age.

Steven A. Goldstein, professor of surgery in the U-M Medical School and professor of biomedical engineering in the U-M College of Engineering, suggested his results, while preliminary, raise a “red flag” on the increasing use of human growth hormone in short children and as a “fountain-of-youth drug” in the elderly.

The study by Kuo-Fung Tseng, now with the Veterans General Hospital in Taipei, Taiwan, and Goldstein is published in the April 1998 issue of the Journal of Bone and Mineral Research.

The U-M study was designed to learn more about complex feedback mechanisms between genes and mechanical forces, which control how bones grow and develop. “This balance between structure and function has evolved over years of mammalian evolutionary development to produce bone strong enough for an animal’s daily activity, but not so strong that it requires too much energy to grow and maintain,” Goldstein said. “Disturbances in this well-balanced relationship could result in bone fragility diseases, such as osteoporosis.”

Thirty-nine of the male mice in the U-M study were transgenic—meaning that their DNA contained both mouse and human genes. These mice were able to secrete large amounts of human growth factor, because the human gene which triggers production of this hormone had been inserted into their DNA during the fertilized egg stage of development. Thirty-six male control mice in the study were littermates of the experimental mice, but did not carry the gene for human growth hormone.

According to Goldstein, mean body weights of the two groups were identical until the puberty growth spurt, which begins when mice are between four and nine weeks old. “After 12 weeks of age, the transgenic mice were 25 to 30 percent larger in body weight and size than their littermate controls,” Goldstein said. “At 16 weeks, the femurs or long upper leg bones of the experimental mice were significantly larger, thicker and longer than those of the control mice.” To test for strength and fracture resistance, Tseng and Goldstein removed femurs from both groups of mice and bent them in a mechanical testing device until they broke. While leg bones from transgenic mice were stronger at 16 weeks of age, the smaller leg (more) bones from control mice were just as strong or even stronger by about 24 weeks. “We saw a continual degradation of mechanical properties in the bones of transgenic mice as they aged,” Goldstein said. When they examined cross-sections of bone under a microscope, Tseng and Goldstein found the transgenic mice had more cartilage, woven bone and porous areas in their bone tissue and a lower ash content than did the same bones in age-matched control mice. They also found that transgenic mice had higher levels of bone resorption as they aged than did normal mice. Goldstein said more research will be necessary to pin down exactly how growth hormone upsets the natural balance between structure and function in developing mouse bone. “It may be that inferior bone quality is a direct result of too-rapid bone growth or the presence of growth hormone itself,” Goldstein said. “We believe it’s more likely that the animal’s adaptive feedback mechanism, sensing more stress on bones during the growth spurt, increases bone growth to restore a balance between structure and function. After puberty, the mechanism senses less stress and triggers increased bone resorption to restore the balance again. In the process of maintaining whole bone structural integrity, the mechanical integrity of tissue may be sacrificed.” “While we don’t yet understand exactly how this mechanism works in mice, much less people, it appears that the same process which makes bone grow larger is doing so at the expense of bone quality,” Goldstein said. “Until we know more, I would be cautious about prescribing human growth hormone, especially to individuals without a specific medical need, without giving any thought to the possible consequences.” The study was funded by the National Institutes of Health and the Frederick Fischer Endowment for pediatric orthopedic research at the U-M. Jeffrey F. Bonadio, a senior associate research scientist in the U-M Medical School, also was a key collaborator in the research program.

Steven A. GoldsteinJournal of Bone and Mineral ResearchNational Institutes of Health