Parathyroid Hormone Effect on Facilitating Stress Fracture Repair

Stress fractures (SFx) result from repetitive cyclical loading of bone. They are frequent athletic injuries and underlie atypical femoral fractures following long-term bisphosphonate (BP) therapy. Parathyroid hormone (PTH) and BPs, including Alendronate (ALN), have opposing effects on bone dynamics. ALN is an antiresorptive agent that decreases bone turnover, and with prolonged doses of BP the healing of SFxs is delayed. The extent to which intermittent PTH (iPTH) remains effective in the treatment of SFx in the presence of an ongoing BP treatment has not been tested. Starting 24 hours after SFx induction, the effect of a single PTH injection, and daily iPTH injections for 14 days, on the healing of SFx in the rat ulna was investigated. SFx was induced in 330 female Wistar rats (300 ± 15 g) during a single loading session. In the single PTH injection experiment, rats were divided into two groups (n=60). A single PTH (8 μg/100g) or vehicle (VEH) saline injection was administered 24 hours after loading. Ulnae were examined 1, 2, 6 or 10 weeks following SFx.

In the daily iPTH experiment, rats were divided into two equal groups (n=30) and received either daily iPTH (8 μg/100g/day) for 14 days or equivalent daily VEH injections. In the combined ALN-PTH therapy experiment, rats were divided into five equal groups (n=30), received either, ALN (1 ug/kg/day) for the whole duration of the experiment (ALN1) or only until SFx initiation (ALN2); combined ALN-PTH with continuation (ALN-PTH1) or cessation (ALN-PTH2) of ALN after SFx induction or an equivalent vehicle (VEH) as a control. Ulnae were examined 2 or 6 weeks following SFx. Two Toluidine Blue and TRAP-stained sections of the SFx were examined for histomorphometric analysis using Osteomeasure™ software.

In the single PTH experiment, a significant interaction was observed between the effects of time and type of treatment on osteoclast number (N.Oc) and perimeter (Oc.Pm). This resulted in osteoclast number and perimeter being significantly greater two weeks following PTH treatment (P≤0.001). Most histomorphometric variables were significantly influenced by the main effect of time between the second and sixth weeks. After 6 weeks, bone formation was the main activity in BMUs. A significant negative correlation (r= -0.602) was observed between erosion and healing perimeters in PTH group after 6 weeks (P= 0.038). In the daily iPTH treatment, the results show that daily iPTH injections for 14 days increased SFx remodeling by improving the woven bone architecture. This was evident in the form of a a significantly greater woven bone apposition rate (P = 0.049), woven bone area (P = 0.041) when compared to the daily VEH injection group after 2 weeks of SFx initiation. Compared to the results obtained from the single PTH experiment, daily iPTH injections for 14 days were not superior to a single PTH injection. Despite increasing the recruitment and availability of osteoclasts, daily iPTH injections are not responsible for the transportation of osteoclasts from the BMU to the narrow SFx line. This was demonstrated by the presence of osteoclastic activity within the surrounding woven bone callus that did not translate into a significant effect within the BMU or the SFx line.

In the combined ALN-PTH protocol, there was a significant interaction between the effects of time and treatment type on the woven bone width and woven bone apposition rate. Combined ALN PTH treatment improved woven bone architecture. However, woven bone variables remained unaffected by the cessation or continuation of ALN. Cessation of ALN after SFx induction effectively increased osteoclast number in ALN-PTH2 (ALN cessation) group when compared to ALN PTH1 (ALN continuation) group (P= 0.006), and VEH (P= 0.024) after two weeks. Furthermore, there was a significant interaction between the effects of time and treatment type on the number of osteoclasts per unit BMU are and length. The number of osteoclasts per unit BMU area and length was significantly greater in ALN cessation groups. The combined ALN-PTH treatment was not superior to daily iPTH treatment

It was concluded that a single PTH injection increased osteoclastogenesis by the second week of the remodeling cycle in a SFx in vivo. Intermittent daily PTH injections (iPTH) for 14 days, starting 24 hours after the initiation of SFx, had the same effect on indices of SFx healing as a single PTH injection. The increased number of osteoclasts available around the SFx area was not beneficial. This was related to the limited area available for these cells to be transported from the BMU into the SFx line to produce a more significant effect. It was also concluded that intermittent short duration iPTH treatment effectively increased remodeling of SFx even after BP treatment, provided that BP was ceased at the time of SFx. iPTH injections for 14 days were not sufficient to counteract the effect of a concurrent BP treatment. The results obtained from the current study could potentially help develop shorther iPTH treatment protocols for clinical management of SFxs. It also helps guide clinical decision making to cease BP treatment in cases of SFx. Furthermore, future research using the same treatment protocols from the current study augmented by Vit D, calicium supplements and/or mechanical loading could achieve better treatment outcomes.

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Year

Entry

1979

Parfitt AM. Quantum concept of bone remodeling and turnover: implications for the pathogenesis of osteoporosis. Calcif Tiss Int. 1979;28(1):1-5.

2002

Currey JD. Bones: Structure and Mechanics. Princeton, NJ: Princeton University Press; 2002.

2013

Dallas SL, Prideaux M, Bonewald LF. The osteocyte: an endocrine cell … and more. Endocr Rev. October 2013;34(4):658-690.

2011

Schilcher J, Michaëlsson K, Aspenberg P. Bisphosphonate use and atypical fractures of the femoral shaft. NEJM. May 5, 2011;364(18):1728-1737.

2009

Andersen TL, Sondergaard TE, Skorzynska KE, Dagnaes-Hansen F, Plesner TL, Hauge EM, Plesner T, Delaisse J-M. A physical mechanism for coupling bone resorption and formation in adult human bone. Am J Pathol. January 2009;174(1):239-247.