Commentary & Perspective

Commentary & Perspective on
"Enhancement of Experimental Fracture-Healing by Systemic Administration of Recombinant Human Parathyroid Hormone (PTH 1-34)"
by Yaser M. Alkhiary, BDS, MSD, DSD, et al.

Commentary & Perspective by
Joseph M. Lane, MD*,
Hospital for Special Surgery, New York, NY

Alkhiary and coworkers have presented a three-arm study of parathyroid hormone (PTH) treatment and fracture-healing in a rat femoral injury model. Through the use of biomechanical testing, microquantitative computed tomography, and histological and histomorphometric analyses, the authors have demonstrated that daily systemic administration of PTH (1-34) enhances fracture-healing. The investigators utilized two dosages (5 µg/kg and 30 µg/kg) of PTH (1-34), with the major improvements relating to the higher dosage. But even the lower dosage had significant effects (p < 0.05) at thirty-five days. The authors point out that the 30 µg/kg dosage is well above the human dosage, but that the 5 µg/kg dosage is only three times higher than the currently marketed dosage when correcting for species differences between rats and man. The current study adds to a growing body of investigative studies demonstrating an enhanced healing process in groups receiving intermittent administration of PTH compared with the results seen in matched control groups¹. Thus, intermittent PTH potentially offers the clinician a systemic method to stimulate the bone-healing process, not only for the treatment of fractures but for other applications as well, such as obtaining arthrodesis or in achieving porous ingrowth after implant fixation.

A related question arises: how does PTH compare with bisphosphonates in terms of bone healing/regeneration? Both agents are currently utilized for the treatment of osteoporosis². They equally reduce the risk for low-energy fracture; however, they mitigate the bone loss of osteoporosis through different mechanisms. Bisphosphonates inhibit excessive bone resorption, while PTH is an anabolic agent that stimulates osteoblastic bone formation. In the setting of an uncompromised fracture, bisphosphonates lead to a larger callus but bone maturation is delayed. The net result is no alteration of the overall mechanical strength. PTH, on the other hand, not only increases the size of the callus but also accelerates the maturation process that results in faster healing and improved mechanics of the fracture regenerate.

The results from animal studies have shown that with metaphyseal fractures, the bisphosphonates will impede disuse osteoporosis and not markedly interfere with the healing events³. In contrast, in diaphyseal fractures or in the compromised host, bisphosphonates may delay early and critical osteogenic processes that result in delayed healing⁴. In all circumstances, however, PTH would be expected to augment the repair¹.

Until definitive clinical trials are fully available, it may be wiser to withhold bisphosphonate therapy until the fracture repair/fusion is completed. Conversely, PTH therapy should be initiated, particularly in the setting of potentially compromised healing. There is a pressing need for randomized trials of PTH versus bisphosphonates in the setting of the acute osteoporotic fracture.

*The author did not receive grants or outside funding in support of his research or preparation of this manuscript. He did not receive payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the author is affiliated or associated.

References

1. Andreassen TT, Ejersted C, Oxlund H. Intermittent parathyroid hormone (1-34) treatment increases callus formation and mechanical strength of healing rat fractures. J Bone Miner Res. 1999;14:960-8.
2. Osteoporosis prevention, diagnosis, and therapy. NIH Consens Statement. 2000;17:1-45.
3. van der Poest Clement E, Patka P, Vandormael K, Haarman H, Lips P. The effect of alendronate on bone mass after distal forearm fracture. J Bone Miner Res. 2000;15:586-93.
4. Cao Y, Mori S, Mashiba T, Westmore MS, Ma L, Sato M, Akiyama T, Shi L, Komatsubara S, Miyamoto K, Norimatsu H. Raloxifene, estrogen, and alendronate affect the processes of fracture repair differently in ovariectomized rats. J Bone Miner Res. 2002;17:2237-46.

Copyright © 2005 by the The Journal of Bone and Joint Surgery, Inc.