Parathyroid hormone injection shows faster cartilage and bone formation vs. saline

PTH may boost fracture repair and help to avoid osteoinductive placement surgery.

Issue: December 2006

PHOENIX — Researchers have shown that parathyroid hormone stimulated fracture healing in an animal model and that it may be mediated by the Wnt signaling pathway.

Sanjeev Kakar, MD, of Boston, compared the femoral fracture healing rates of 180 mice that received either saline or 40mg/kg parathyroid hormone (PTH) injections for 14 days. During a 28-day follow-up, Kavar and his colleagues discovered that the PTH-treated group demonstrated enhanced hypertrophic chondrocyte maturation and faster cartilage turnover than the controls. They discovered significantly more mineralized tissue formed at day 10 in the PTH-treated group, compared to the controls Kakar said during his presentation at the Orthopaedic Trauma Association annual meeting. They also found that markers for collagen II, X and matrix metalloproteinase-9 were activated 3 days earlier in the PTH-injected mice (both day 7 vs. day 10).

The researchers also demonstrated that this PTH of fracture repair might be via the Wnt signaling pathways that stimulate chondroprogenitor cells. "Basically what we saw was that early on in the repair process, namely during chondrogenesis, Wnts 4, Wnt 5a and Wnt 5b were upregulated as early as day 3, whereas during osteogenesis Wnt 10b, LRP5 and LRP6 were predominately involved," Kakar told Orthopedics Today.

The researchers collected samples from the specimens at days 2, 3, 5, 7, 10, 14, 21 and 28 and performed histological, radiological and molecular analysis. They examined SOX-9 and collagen X and II expressions to determine chrondrocyte activity, and used Runx2, collagen I and osteocalcin as markers for osteoblast function.

"We demonstrated that there was an increase in cross-sectional area, callus length and bone volume seen in the PTH-treated groups compared to the controls," Kakar told Orthopedics Today. In the study, the investigators also found 19% more collagen II and a 16% more collagen X in the PTH-treated group compared to the saline group. The PTH-injected cohort also demonstrated 6% more osteocalcin. SOX-9 and Runx2 activity also increased earlier in the PTH-treated mice, suggesting that PTH may be stimulating chondroprogenitor cell recruitment and maturation, Kakar said.

"The take-home message from this study is that as a systemic agent, PTH may be able to provide a means of stimulating fracture repair without the need for additional surgery to place an osteoconductive or osteoinductive agent locally at the fracture site," Kakar said. "It appears to be acting during the early part of the repair process, thereby enhancing fracture healing."

He said that future animal studies would determine the optimal dosage of PTH and the best time of administration.

"Now, we're doing a study that we're going to give it at staggered times during the early stages of repair to see which time-point correlates best to stimulate the healing repair process," he said.

For more information:
Kakar S, Barnes GL, Al-Sebaei M, et al. Molecular mechanisms of parathyroid hormone-mediated enhancement of fracture repair. #46. Presented at the Orthopaedic Trauma Association 22nd Annual Meeting. Oct. 4-7, 2006. Phoenix.
Sanjeev Kakar, MD, is a resident fellow at the Orthopaedic Research Laboratory at Boston University Medical Center, 715 Albany Street, R-205, Boston MA 02118. He can be reached at (617) 414-1664, fax: 617-414-1661or sanjeev.kakar@bmc.org. He has indicated that he has no financial conflict of interest to declare.
The study was funded by the Orthopedic Research and Education Foundation, Orthopedic Trauma Association and the Association of Bone and Joint Surgeons.