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Combining systemic and local osteoporosis treatments: A longitudinal in vivo microCT study in ovariectomized rats
Vincent A Stadelmann1, Estelle Gerossier2, Ulrike Kettenberger3
1Department of Research and Development, Schulthess Klinik, Zürich, Switzerland.
Introduction:
Managing osteoporotic patients at immediate fracture risk is challenging, in part due to the slow and localized effects of anti-osteoporotic drugs. Combining systemic anti-osteoporotic therapies with local bone augmentation techniques offers a promising strategy, but little is known about potential interactions. We hypothesized that integrating systemic treatments with local bone-strengthening biomaterials would have an additive effect on bone density and structure. This study investigated interactions and synergies between systemic therapies and injectable biomaterials, HA2 and HA2-ZOL, designed for local bone strengthening. HA2-ZOL incorporates Zoledronate, a bisphosphonate, to enhance anti-resorptive effects. These materials were tested in an in vivo rat model of osteoporosis using microCT and histology.
Methods:
Thirty-six ovariectomized Wistar rats were treated systemically with vehicle (VEH), alendronate (ALN), or parathyroid hormone (PTH). One week later, their tibiae were randomly assigned to local treatment groups: HA2, HA2-ZOL, or NaCl control. Bilateral injections targeted metaphyseal trabecular bone, with microCT scans tracking changes over 8 weeks. Regions of interest (ROIs) were identified and analyzed for bone volume fraction (BV/TV), tissue mineral density (TMD), and trabecular morphology. Histological analyses were performed at week 8 to assess bone structure and mineral inclusions.
Results:
VEH animals with NaCl injections experienced marked bone loss, partially mitigated by ALN and PTH. HA2 injections increased BV/TV by factors of 2.5 to 3.4 across treatments compared to baseline, with effects confined to the injected material. HA2-ZOL amplified this response, with BV/TV increases up to 4.8-fold, particularly in VEH and PTH animals. The effects peaked at 2-4 weeks post-injection, followed by remodeling and restoration. Both local treatments increased trabecular thickness, with HA2-ZOL showing slower post-peak resorption.
Discussion:
HA2 injections significantly densified bone, independent of systemic therapy. Zoledronate in HA2-ZOL enhanced bone formation and delayed resorption in control and PTH animals, but offered no additional benefit when combined with systemic bisphosphonate. These findings support the hypothesis of an additive effect, suggesting that injectable hydrogels with localized drug delivery can complement systemic therapies by rapidly increasing local bone density, thereby potentially preventing fractures in high-risk osteoporotic patients.
Insights
Injectable biomaterials like HA2 and HA2-ZOL significantly increased bone density in an osteoporosis model. Combining local treatments with systemic therapies showed additive effects, potentially preventing fractures in at-risk patients.
Area of Science:
- Biomaterials Science
- Orthopedic Research
- Pharmacology
Background:
- Osteoporosis management is challenging due to slow-acting systemic drugs.
- Combining local bone augmentation with systemic therapy is a promising strategy.
- Interactions between systemic treatments and local biomaterials require investigation.
Purpose of the Study:
- To investigate interactions and synergies between systemic therapies and injectable biomaterials (HA2, HA2-ZOL) for local bone strengthening.
- To assess the additive effect on bone density and structure in an in vivo osteoporosis model.
Main Methods:
- Ovariectomized rats received systemic treatments (vehicle, alendronate, parathyroid hormone).
- Tibiae were injected with HA2, HA2-ZOL, or NaCl control.
- MicroCT and histology analyzed bone volume fraction, mineral density, and morphology over 8 weeks.
Main Results:
- HA2 injections increased bone volume fraction (BV/TV) 2.5-3.4 fold, independent of systemic therapy.
- HA2-ZOL further amplified BV/TV increases up to 4.8 fold, especially in vehicle and PTH groups.
- Both treatments increased trabecular thickness, with HA2-ZOL showing delayed resorption.
Conclusions:
- Injectable HA2 hydrogels significantly increased local bone density, complementing systemic osteoporosis treatments.
- HA2-ZOL demonstrated enhanced bone formation and delayed resorption, particularly when combined with PTH.
- This approach offers a strategy to rapidly increase bone density and potentially prevent fractures in high-risk patients.
