Parathyroid Hormone (1–34) Transiently Protects Against Radiation-Induced Bone Fragility

Abstract

Radiation therapy for soft tissue sarcoma or tumor metastases is frequently associated with damage to the underlying bone. Using a mouse model of limited field hindlimb irradiation, we assessed the ability of parathyroid hormone (1–34) fragment (PTH) delivery to prevent radiation-associated bone damage, including loss of mechanical strength, trabecular architecture, cortical bone volume, and mineral density. Female BALB/cJ mice received four consecutive doses of 5 Gy to a single hindlimb, accompanied by daily injections of either PTH or saline (vehicle) for 8 weeks, and were followed for 26 weeks. Treatment with PTH maintained the mechanical strength of irradiated femurs in axial compression for the first eight weeks of the study, and the apparent strength of irradiated femurs in PTH-treated mice was greater than that of naïve bones during this time. PTH similarly protected against radiation-accelerated resorption of trabecular bone and transient decrease in mid-diaphyseal cortical bone volume, although this benefit was maintained only for the duration of PTH delivery. Overall, PTH conferred protection against radiation-induced fragility and morphologic changes by increasing the quantity of bone, but only during the period of administration. Following cessation of PTH delivery, bone strength and trabecular volume fraction rapidly decreased. These data suggest that PTH does not negate the longer-term potential for osteoclastic bone resorption, and therefore, finite-duration treatment with PTH alone may not be sufficient to prevent late onset radiotherapy-induced bone fragility.

Altered mechanical behavior of demineralized bone following therapeutic radiation

“…Using a mouse model of unilateral hindlimb limited field radiotherapy, we have previously demonstrated that therapeutic radiation results in loss of femoral metaphyseal trabecular structures (decreased trabecular bone volume fraction, decreased trabecular number, decreased connectivity density, and increased trabecular spacing) subsequent to increased osteoclastic activity, diminished bone strength (axial compression testing of distal femur, femoral diaphyseal bending strength), and decreased femoral diaphyseal fracture toughness without loss of bone density. [11][12][13][14] Work in other labs has supported these findings. [15][16][17] Furthermore, we have shown that the bone matrix (organic and collagen phases) becomes increasingly aligned post-RTx, accompanied by an increase in trivalent:divalent collagen crosslink ratio as measured by Raman spectroscopy, with only small transient changes in pathologic crosslinks and adducts such as advanced glycation end products (AGEs).…”

Longitudinal Effects of Single Hindlimb Radiation Therapy on Bone Strength and Morphology at Local and Contralateral Sites

“…Work in mouse models (total body and limited field RTx) consistently demonstrates an early increase in osteoclast numbers at 1 to 2 weeks post‐RTx, followed by long‐term depletion of osteoclasts . This results in early loss of trabecular bone and persistence of highly cross‐linked, highly aligned bone matrix due to loss of remodeling activity . At this point, it is unknown whether loss of local osteoclasts after limited field irradiation is because of 1) the absence of osteoclast progenitor cells, or 2) an inability of osteoclast precursors to multinucleate, differentiate, or adhere.…”

“…(9,10) This results in early loss of trabecular bone and persistence of highly cross-linked, highly aligned bone matrix due to loss of remodeling activity. (16,17,21,33) At this point, it is unknown whether loss of local osteoclasts after limited field irradiation is because of 1) the absence of osteoclast progenitor cells, or 2) an inability of osteoclast precursors to multinucleate, differentiate, or adhere. Using this mouse model, we have previously shown that mineral apposition rate is not decreased post-RTx.…”

Bench to Bedside: Animal Models of Radiation Induced Musculoskeletal Toxicity

“…Based on its use in severely osteoporotic patients, intermittent administration of parathyroid hormone may be a useful drug to decrease bone loss and reduce the risk of fracture. The use of PTH has been investigated in a series of studies by Oest and colleagues [51,75]. In the first, they investigated the impact of PTH on bone fragility in a mouse hind limb model.…”