New technologies for the enhancement of skeletal repair have led to the development of biophysical modalities such as electrical and ultrasound stimulation devices and locally implantable or injectable therapies such as calcium phosphate or calcium sulfate-based bone graft substitutes, recombinant bone morphogenetic proteins, and allogeneic or autologous stem cell products. Ongoing research may yield additional locally delivered materials, including a variety of growth factors (e.g., platelet-derived growth factor, fibroblast growth factor, and vascular endothelial growth factor), Wnt proteins, prostaglandin receptor agonists, and others. However, while these therapies may enhance skeletal repair by direct application at or adjacent to a fracture site, the application of systemically administered pharmaceuticals could establish a new paradigm for adjunctive fracture care and could have widespread appeal. In this issue of The Journal, Peichl et al. report on the successful use of parathyroid hormone (PTH) 1-84 for this purpose. This report now joins the growing body of clinical evidence that a recombinant PTH peptide can improve the healing of bone1-3.
In this investigation, sixty-five osteoporotic women who had fractures of the pubic and/or ischial rami of the pelvis were recruited chronologically and every third patient (n = 21) was assigned to receive a once-daily injection of 100 μg of PTH 1-84. Forty-four patients were assigned to a control group. All patients received 1000 mg of calcium and 800 IU of vitamin D. As the mean age of the patients was 82.8 years, these doses of calcium and vitamin D are consistent with current recommendations by the Institute of Medicine for the most elderly patients4. Moreover, because these patients were managed for severe osteoporosis with a T-score of below −2.5, treatment was continued for twenty-four months after the fracture had healed. Computed tomography scans were done at the time of enrollment in this study, as well as every fourth week, until evidence of cortical bridging at the fracture site was confirmed. Functional outcome was assessed with use of a visual analog scale for pain and a Timed "Up and Go" test. The results showed that all twenty-one patients who were managed with PTH 1-84 had fracture-healing at a mean 7.8 weeks after treatment, whereas the control patients had healing at approximately 12.6 weeks (p < 0.001). At Week 8, all fractures in the treatment group and only four fractures in the control group were healed (healing rate, 100% compared with 9.1%; p < 0.001). Both measurements of functional outcome were improved in the treatment group compared with controls (p < 0.001). Importantly, no adverse events or deaths were recorded during the study period. The authors concluded that, in elderly patients with osteoporosis, PTH 1-84 accelerates fracture-healing in pelvic fractures and improves functional outcome.
The findings of this study are important and impressive in several ways. First, low-energy pelvic fractures are a common problem among elderly osteoporotic women and lead to pain with difficulty in mobilization and are associated with exacerbation of comorbid conditions. A systemic therapy to accelerate recovery from this injury would be a major step forward. Second, although this study was performed in elderly patients with osteoporosis, and although different parathyroid hormone peptides have been investigated for their anabolic effects in the treatment of post-menopausal osteoporotic women, the question of the generalizability of this class of compounds to the enhancement of skeletal repair in younger age groups and in men raises interesting possibilities. Indeed, preclinical studies with PTH analogues in growing animals have suggested enhancement of fracture-healing in long bones3 and the improvement of porous ingrowth into orthopaedic implants5.
Parathyroid hormone is an eighty-four-amino acid polypeptide whose essential role is to regulate the metabolism of calcium and phosphate. During mineral homeostasis, PTH responds to systemic demands to increase serum calcium levels by enhancing gastrointestinal calcium absorption, increasing renal calcium and phosphate reabsorption, and liberating calcium from the skeleton. However, while the most well-recognized effect of this hormone is to increase bone resorption, the response of osteoclasts to PTH is most likely mediated by the osteoblast as the receptors for PTH are found on osteoblasts and not on osteoclasts. Moreover, studies have shown that continuous exposure to PTH leads to an increase in osteoclast density and activity whereas intermittent exposure stimulates osteoblasts and results in increased bone formation6. Thus, a once-daily injection of PTH should produce an anabolic effect on the skeleton, and it is now hypothesized that this effect may be recruited to enhance the repair of skeletal tissues7. Both preclinical and clinical studies have been conducted with use of recombinant forms of the full-length molecule (amino acids 1 through 84, as in this report, as well as the active site component, amino acids 1 through 34). PTH 1-84 is approved for the treatment of severe osteoporosis in Europe, whereas PTH 1-34 or teriparatide is approved in the United States and other countries. Both substances are administered by means of daily standard subcutaneous injection. I am not aware of any comparative studies regarding the clinical use of these drugs.
The study by Peichl et al. does have some limitations. First, although prospectively designed, patients were not truly randomized but rather were recruited chronologically such that every third patient was assigned to treatment with PTH 1-84. In addition, sample sizes and patient allocation were unbalanced (twenty-one patients in the treatment group, compared with forty-four patients in the control group) and all patients managed with PTH 1-84 were from a single center whereas the control patients were recruited from that center as well as one other. These issues, while seemingly minor, do introduce a level of concern regarding the quality of the evidence.
Recently, an acceleration of fracture-healing with teriparatide (PTH 1-34) was reported in a randomized controlled trial of 102 postmenopausal women who had sustained a distal radial fracture that was in need of closed reduction but not operative treatment1. The primary outcome measure in that study was the estimated median time from the fracture to the first radiographic evidence of complete cortical bridging in three of the four cortices. Indeed, while teriparatide showed a significant acceleration of healing in patients managed with 20 μg per day (p = 0.006), those managed with the higher dose (40 μg per day) showed no difference in healing time when compared with patients who had been managed with placebo. As a result of this unusual finding, the authors concluded that their results must be interpreted with caution. Indeed, concern has been expressed regarding the selection of the fracture site for this clinical trial as even the most experienced surgeons and radiologists recognize the difficulty of assessing the healing of distal radial fractures on the basis of cortical bridging on radiographs alone. In the study by Peichl et al., the assessment of fracture-healing included not only radiographic review but also enhanced imaging with computed tomography.
The growing body of evidence that PTH peptides not only increase bone mass in osteoporotic patients but may also have a role to play in the enhancement of skeletal repair is exciting. With consistently positive preclinical studies and now several preliminary clinical reports, the pharmaceutical industry is well positioned to partner with orthopaedic investigators to pursue the appropriate clinical trials and necessary regulatory pathways that would support approval of a PTH peptide for the treatment of skeletal injuries. The ability to administer a systemic agent that would potentiate a skeletal repair process would represent a major advance for patients with skeletal injuries.