Parathyroid hormone's enhancement of bones' osteogenic response to loading is affected by ageing in a dose- and time-dependent manner

Abstract

Decreased effectiveness of bones' adaptive response to mechanical loading contributes to age-related bone loss. In young mice, intermittent administration of parathyroid hormone (iPTH) at 20–80 μg/kg/day interacts synergistically with artificially applied loading to increase bone mass. Here we report investigations on the effect of different doses and duration of iPTH treatment on mice whose osteogenic response to artificial loading is impaired by age. One group of aged, 19-month-old female C57BL/6 mice was given 0, 25, 50 or 100 μg/kg/day iPTH for 4 weeks. Histological and μCT analysis of their tibiae revealed potent iPTH dose-related increases in periosteally-enclosed area, cortical area and porosity with decreased cortical thickness. There was practically no effect on trabecular bone. Another group was given a submaximal dose of 50 μg/kg/day iPTH or vehicle for 2 or 6 weeks with loading of their right tibia three times per week for the final 2 weeks. In the trabecular bone of these mice the loading-related increase in BV/TV was abrogated by iPTH primarily by reduction of the increase in trabecular number. In their cortical bone, iPTH treatment time-dependently increased cortical porosity. Loading partially reduced this effect. The osteogenic effects of iPTH and loading on periosteally-enclosed area and cortical area were additive but not synergistic. Thus in aged, unlike young mice, iPTH and loading appear to have separate effects. iPTH alone causes a marked increase in cortical porosity which loading reduces. Both iPTH and loading have positive effects on cortical periosteal bone formation but these are additive rather than synergistic.

Examining the influence of PTH(1-34) on tissue strength and composition

“…As a result, local changes in tissue composition following PTH(1–34) treatment have the potential to enhance mechanotransduction indirectly by augmenting the mechanical stimuli osteocytes experience during physical activity. This is consistent with the additive effect PTH(1–34) treatment on bone adaptation during in-vivo loading or treadmill exercise [50–52]. However, the additive effect provided by PTH(1–34) treatment is readily considered a function of PTH altering the cellular response to mechanical stimuli as well as its down-stream activation of similar anabolic mechanisms [53, 54].…”

Aging and Mechanoadaptive Responsiveness of Bone

“…Meakin et al (2017) reported accrual of the cortical bone in response to intermittent PTH treatment (iPTH), which additionally generated positive loadrelated osteogenic interactions in young mice. Aged mice, in contrast, exhibited no positive load-iPTH interaction in the cortical compartment [88] suggesting that aged bones have reduced sensitivity to pharmacotherapy and mechanical loading. With view to better ascertain the role of osteoclasts in aged bones, Naruse et al (2016) compared the efficacy of alendronate as a means of restricting bone loss in aged female rats, which were sedentary, estrogendeficient, or both.…”

Intermittent Parathyroid Hormone Accelerates Stress Fracture Healing More Effectively Following Cessation of Bisphosphonate Treatment

“…(48) The significant increase in osteoclast number along the SFx was expected at 2 weeks following PTH treatment. (31,49,50) This may be explained by the PTH induction of monocyte chemotactic protein-1, which is responsible for differentiation and recruitment of osteoclast precursors in early remodeling phases. (51,52) The mechanism of the anabolic action of PTH is also supported by other factors, including calcium availability and the calcium sensing receptor.…”