Abstract
ABSTRACTParathyroid hormone (PTH) and bisphosphonates (BPs), including alendronate (ALN), have opposing effects on bone dynamics. The extent to which PTH remains effective in the treatment of stress fracture (SFx) in the presence of an ongoing BP treatment has not been tested. SFx was induced in 150 female Wistar rats, divided into five equal groups (n = 30). All rats were pretreated with ALN (1 μg/kg−1/day−1) for 14 days prior to SFx induction, followed by ALN cessation or continuation for the duration of the experiment; this was combined with daily PTH (8 μg/100 g−1/day−1) on SFx induction for 14 days, followed by cessation or continuation of ALN after SFx induction or an equivalent vehicle as a control. Ulnas were examined 2 weeks or 6 weeks following SFx. Two toluidine blue‐ and two tartrate‐resistant acid phosphatase‐stained sections were examined for histomorphometric analysis using Osteomeasure software. There was a significant interaction between the effects of time and treatment type on the woven bone width and apposition rate, as well as an improvement in the woven bone architecture. However, woven bone variables remained unaffected by the cessation or continuation of ALN. Cessation of ALN increased osteoclast number when compared with the ALN‐PTH continuation group (p = 0.006), and vehicle (p = 0.024) after 2 weeks. There was a significant interaction between the effects of time and treatment type on the number of osteoclasts per unit BMU area and length. The number of osteoclasts per unit BMU area and length was significantly greater in ALN cessation groups. It was concluded that intermittent short‐duration iPTH treatment effectively increased remodeling of SFx with a concurrent BP treatment, provided that BP was ceased at the time of SFx. Our results could help develop shorter iPTH treatment protocols for the clinical management of SFxs and guide clinical decision‐making to cease BP treatment in cases of SFx. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.
Highlights
IntroductionThe main difference between SFx and acute fractures is related to the nature of loading of the bones
Stress fractures (SFx) account for about 1%-7% of all athletic injuries [1,2]
There were no significant differences among groups in terms of cortical bone area (CT.B.Ar) and cortical perimeter (Ct.Pm), woven bone area (Wo.B.Ar, mm2), and the length of stress fracture (SFx.Le, μm)
Summary
The main difference between SFx and acute fractures is related to the nature of loading of the bones. Bisphosphonates (BPs) are stable analogues of pyrophosphatase. They are deposited on bone surfaces within minutes or hours of uptake. The mode of action on the osteoclast is radically different between non-nitrogen containing BPs (first generation) and nitrogen-containing BPs (2nd and 3rd generation). Apoptosis is induced by non-nitrogen containing BP through formation of a toxic analogue of adenosine triphosphate; whereas nitrogen-containing BPs (2nd and 3rd generation) target the enzyme farnesyl diphosphate synthase needed for post-translational modification of small GTP-binding proteins required for osteoclastic function [3,4]. Regardless of the inhibitory pathway, all BPs depress osteoclast activation and resorption [4]
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