Enhanced Individual Trabecular Repair and Its Mechanical Implications in Parathyroid Hormone and Alendronate Treated Rat Tibial Bone

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Postmenopausal osteoporosis is often treated with bisphosphonates (e.g. alendronate, ALN), but over-suppression of bone turnover by long-term bisphosphonate treatment may decrease bone tissue heterogeneity. Thus, alternate treatment strategies after long-term bisphosphonates are of great clinical interest. The objective of the current study is to determine the effect of intermittent parathyroid hormone (PTH) following 12 weeks of alendronate (ALN, a bisphosphonate) treatment in 6-month-old, ovariectomized (OVX) rats on bone microarchitecture, bone remodeling dynamics, and bone mechanical properties at multiple length scales. By using in vivo μCT and 3D in vivo dynamic bone histomorphometry techniques, we demonstrated the efficacy of PTH following ALN therapy for stimulating new bone formation, and increasing trabecular thickness and bone volume fraction. In healthy bone, resorption and formation are coupled and balanced to sustain bone mass. OVX results in resorption outpacing formation, and subsequent bone loss and reduction in bone tissue modulus and tissue heterogeneity. We showed that ALN treatment effectively reduced bone resorption activity and regained the balance with bone formation, preventing additional bone loss. However, ALN treatment also resulted in significant reductions in the heterogeneity of bone tissue mineral density and tissue modulus. On the other hand, PTH treatment was able to shift the bone remodeling balance in favor of formation, with or without a prior treatment with ALN. Moreover, by altering the tissue mineralization, PTH alleviated the reduction in heterogeneity of tissue material properties induced by prolonged ALN treatment. Furthermore, switching to PTH treatment from ALN improved bone’s post-yield mechanical properties at both the whole bone and apparent level compared to ALN alone. The current findings suggest that intermittent PTH treatment should be considered as a viable treatment option for patients with prior treatment of bisphosphonates.

Section: Discussionmentioning

confidence: 78%

Intermittent Parathyroid Hormone After Prolonged Alendronate Treatment Induces Substantial New Bone Formation and Increases Bone Tissue Heterogeneity in Ovariectomized Rats

Altman-Singles

Jeong

Tseng

et al. 2017

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“…registered subvolumes through an individual trabecular dynamics (ITD) analysis, as described previously. (30) Briefly, the trabecular rods and plates were isolated using individual trabecular segmentation (ITS) analysis, (33) and the two registered subvolumes were compared to identify incidences of rod disconnection and plate perforation (measures of structural deterioration) and rod connection and plate perforation filling (measures of structural repair). (30) Additionally, the bone formation and resorption rates were also measured based on the registered subvolumes through in vivo dynamic bone histomorphometry analysis.…”

Section: Trabecular Dynamics Analysismentioning

confidence: 99%

Adaptations in the Microarchitecture and Load Distribution of Maternal Cortical and Trabecular Bone in Response to Multiple Reproductive Cycles in Rats

Bakker

Altman-Singles

et al. 2017

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Pregnancy, lactation, and weaning result in dramatic changes in maternal calcium metabolism. In particular, the increased calcium demand during lactation causes a substantial degree of maternal bone loss. This reproductive bone loss has been suggested to be largely reversible, as multiple clinical studies have found that parity and lactation history have no adverse effect on post-menopausal fracture risk. However, the precise effects of pregnancy, lactation, and post-weaning recovery on maternal bone structure are not well understood. Our study aimed to address this question by longitudinally tracking changes in trabecular and cortical bone microarchitecture at the proximal tibia in rats throughout three cycles of pregnancy, lactation, and post-weaning using in vivo μCT. We found that the trabecular thickness underwent a reversible deterioration during pregnancy and lactation, which was fully recovered after weaning, while other parameters of trabecular microarchitecture (including trabecular number, spacing, connectivity density, and structure model index) underwent a more permanent deterioration which recovered minimally. Thus, pregnancy and lactation resulted in both transient and long-lasting alterations in trabecular microstructure. In the meantime, multiple reproductive cycles appeared to improve the robustness of cortical bone (resulting in an elevated cortical area and polar moment of inertia), as well as increase the proportion of the total load carried by the cortical bone at the proximal tibia. Taken together, changes in the cortical and trabecular compartments suggest that while rat tibial trabecular bone appears to be highly involved in maintaining calcium homeostasis during female reproduction, cortical bone adapts to increase its load-bearing capacity, allowing the overall mechanical function of the tibia to be maintained.

“…Individual trabecular segmentation (ITS) analysis (29) was applied to isolate individual trabecular rod-like and plate-like elements, and changes in the volume, thickness, and connectivity of each trabecula over the first 4 weeks post-OVX were tracked through individual trabecular dynamics (ITD) analysis (27) (Figure 4A). Consistent with microstructural findings, virgin rats underwent a substantially higher rate of bone loss over the first 4 weeks post-OVX than reproductive rats (Figure 4B).…”

Section: Resultsmentioning

confidence: 99%

“…For each rat, sequential μCT images were registered to precisely align the trabecular features, as described in (20,25,26) , and a 1.5×1.5×1 mm trabecular subvolume located 1 mm distal to the growth plate was extracted from μCT images at 0 and 4 weeks post-OVX. The post-OVX changes of each individual trabecula, such as percent bone loss due to trabecular thinning, rod disconnection, or plate perforation, were quantified through an individual trabecular dynamics (ITD) analysis, as described in (27) . Trabeculae from all virgin or reproductive rats were pooled together, resulting in a total of 4,752 trabeculae in the virgin and 1,564 trabeculae in the reproductive group.…”

Section: Methodsmentioning

confidence: 99%

Structural Adaptations in the Rat Tibia Bone Induced by Pregnancy and Lactation Confer Protective Effects Against Future Estrogen Deficiency

Bakker

Zhao

et al. 2018

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The female skeleton undergoes substantial structural changes during the course of reproduction. Although bone mineral density recovers postweaning, reproduction may induce permanent alterations in maternal bone microarchitecture. However, epidemiological studies suggest that a history of pregnancy and/or lactation does not increase the risk of postmenopausal osteoporosis or fracture and may even have a protective effect. Our study aimed to explain this paradox by using a rat model, combined with in vivo micro-computed tomography (μCT) imaging and bone histomorphometry, to track the changes in bone structure and cellular activities in response to estrogen deficiency following ovariectomy (OVX) in rats with and without a reproductive history. Our results demonstrated that a history of reproduction results in an altered skeletal response to estrogen-deficiency-induced bone loss later in life. Prior to OVX, rats with a reproductive history had lower trabecular bone mass, altered trabecular microarchitecture, and more robust cortical structure at the proximal tibia when compared to virgins. After OVX, these rats underwent a lower rate of trabecular bone loss than virgins, with minimal structural deterioration. As a result, by 12 weeks post-OVX, rats with a reproductive history had similar trabecular bone mass, elevated trabecular thickness, and increased robustness of cortical bone when compared to virgins, resulting in greater bone stiffness. Further evaluation suggested that reproductive-history-induced differences in post-OVX trabecular bone loss were likely due to differences in baseline trabecular microarchitecture, particularly trabecular thickness. Rats with a reproductive history had a larger population of thick trabeculae, which may be protective against post-OVX trabecular connectivity deterioration and bone loss. Taken together, these findings indicate that reproduction-associated changes in bone microarchitecture appear to reduce the rate of bone loss induced by estrogen deficiency later in life, and thereby exert a long-term protective effect on bone strength. © 2018 American Society for Bone and Mineral Research.