Researchers supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) have uncovered why combining the bone-building treatment parathyroid hormone (PTH) with alendronate, a drug that slows bone loss, is no better than PTH alone. Their work, published in a recent issue of Cell Stem Cell, further suggests that altering the timing and sequence of these therapies could optimize their impact on bone.
Bone is constantly remodeling itself in a tightly coupled process where old bone is removed, or resorbed, and new bone forms in its place. In healthy adults, formation and resorption are synchronized so that new bone replaces old bone in the right quantity, at the right time, and in the right place. When bone formation fails to keep pace with bone resorption, bone loss and, eventually, osteoporosis result.
Most osteoporosis therapies, including alendronate, work by inhibiting bone resorption, while PTH stimulates bone formation. Interestingly, clinical studies using both drugs simultaneously have shown that the effects of PTH are impaired by the addition of alendronate. Building on this work, NIAMS-funded investigator Xu Cao, Ph.D., from the Johns Hopkins University, sought to understand the mechanism by which alendronate blunts PTH’s effects.
In previous studies, Dr. Cao and his team found that the active form of a protein called TGF-?1 (transforming growth factor beta-1) plays a major role in regulating bone resorption by recruiting skeletal stem cells from bone marrow to resorption sites, where they differentiate into bone-building cells called osteoblasts.
In the current study, they discovered that alendronate inhibits the release of active TGF-?1 into the bone marrow, which decreases the recruitment of a subset of skeletal stem cells to bone resorption sites. In experiments with mice, the team found that – as was the case in humans – PTH or alendronate alone increased bone mass, but the combined use of the drugs resulted in no significant improvement in bone mass beyond that produced by the individual drugs. Analysis of the animals’ bones revealed that PTH increased the number of bone-building osteoblasts present at bone remodeling sites, but this increase was not obvious in animals that received both drugs.
The researchers’ discovery supports the notion that bone resorption is necessary for PTH-induced bone formation, and that the timing and sequence of antiresorptive and bone-building therapies could be important for optimal outcomes. For example, they suggest that the use of PTH before alendronate could be a more effective approach than the reverse sequence. Additionally, these new insights could help guide the direction of future osteoporosis therapies.
The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the U.S. Department of Health and Human Services’ National Institutes of Health (NIH), is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about the NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS website at https://www.niams.nih.gov. For more information on osteoporosis and bone health, call the NIH Osteoporosis and Related Bone Diseases ~ National Resource Center (NRC) at (202) 223-0344 or (800) 624-2663 (free call) or visit the NRC website at https://www.bones.nih.gov.
Inhibition of Sca-1-positive skeletal stem cell recruitment by alendronate blunts the anabolic effects of parathyroid hormone on bone remodeling. Wu X, Pang L, Lei W, Lu W, Li J, Li Z, Frassica FJ, Chen X, Wan M, Cao X. Cell Stem Cell. 2010 Nov 5;7(5):571-80.