Deleterious Effects of Intermittent Recombinant Parathyroid Hormone on Cartilage Formation in a Rabbit Microfracture Model: A Preliminary Study

Abstract

Intermittent parathyroid hormone administration can enhance fracture healing in an animal model. Despite the success of exogenous parathyroid hormone on fracture healing and spine fusion, few studies have examined the role of parathyroid hormone on cartilage formation. We determined the effects of intermittent parathyroid hormone on cartilage formation in a rabbit microfracture model of cartilage regeneration. Twelve rabbits were divided into three equal groups: (1) microfracture alone, (2) microfracture + parathyroid hormone daily for 7 days, and (3) microfracture + parathyroid hormone for 28 days. Nonoperated contralateral knees were used as controls. The animals were sacrificed at 3 months and gross and histologic analysis was performed. The microfracture alone group demonstrated the most healing on gross and histologic analysis. Treatment with either 1 or 4 weeks of parathyroid hormone inhibited cartilage formation. Although discouraging from a cartilage repair point of view, this study suggests that the role parathyroid hormone administration has in clinical fracture healing must be examined carefully. Although parathyroid hormone is beneficial to promote healing in spine fusion and midshaft fractures, its deleterious effects on cartilage formation suggests that it may have adverse effects on the outcomes of periarticular fractures such as tibial plateau injuries that require cartilage healing for a successful clinical outcome.

Intermittent PTHrP(1–34) Exposure Augments Chondrogenesis and Reduces Hypertrophy of Mesenchymal Stromal Cells

“…The principal receptor-binding domain of PTHrP lies within amino acids (aa) 15-34, but the first 2 amino acids of PTH/PTHrP are essential for the activation of the cAMP/PKA-dependent pathway. The C-terminus of PTH/PTHrP , where PTH and PTHrP share structural rather than sequential homology, contains a domain necessary for PKC activation within aa [28][29][30][31][32][33][34]. N-terminally truncated peptide analogs such as PTHrP can bind to the receptor but do not elicit a cAMP/PKA response [14].…”

“…Few studies reported on an improved osteochondral repair [28,29], stimulation of chondrogenesis in bone healing during callus formation [30], and inhibition of osteoarthritis progression in an in vitro and in vivo azacytidine-induced osteoarthritis model [31]. In contrast, an inhibition of cartilage formation was observed in a microfracture study after intermittent treatment with PTH [32].…”

Adjuvant therapies for the enhancement of microfracture technique in cartilage repair

“…That was the case of subcutaneously injected recombinant (1-34) PTH. 19 Notably, the findings of the study concerning the final outcome were opposite from the desired, as systemic administration of PTH led to induction of bone formation. On the other hand, the same findings indicate that systemic administration as a delivery method could prove rather effective.…”

“…Histologic and gross analysis showed that treatment with either 1 or 4 weeks of intermittent parathyroid hormone inhibited cartilage formation. 19…”

Microfracture and Augments

“…55 Feeley reported on the negative influence of postoperative parathyroid hormone treatment on cartilage formation in a rabbit microfracture model and recommended against its use. 56…”