Bisphosphonates Alter on Osteoblast Transcripts

Objectives: Bisphosphonates are a class of drugs that work primarily by inhibiting the activity of osteoclasts, and thereby inhibiting bone resorption. These drugs have a high affinity for bone tissue, and bisphosphonates promote the apoptosis of osteoclasts actively engaged in the degradation of mineral on the bone surface and are used to treat osteoporosis, Paget’s disease of bone, osteogenesis imperfecta, and bone metastases. Their ability to reduce bone turnover and increase bone mineral density makes them effective in preserving bone structure and reducing the risk of fractures in pathologic conditions. However, intravenous bisphosphonates have been associated with Medication Related Osteonecrosis of the Jaw (MRONJ), characterized by death of bone tissue of the jaw especially after trauma (including implant placement and extractions). The purpose of this study was to examine the effects of bisphosphonates on bone building cells (osteoblasts).
Methods: Rat osteosarcoma cells (UMR-106) were treated for 24 hours with various concentrations of bisphosphonates (zoledronate, clodronate and pyrophosphate). Cell survival was assessed fluorometrically using Calcein-AM. Transcript expression was assayed via RT-PCR. Cell proliferation was assessed fluorometrically using Cyquant™.
Results: Concentrations of up to 20 μM of all three bisphosphonates did not reduce cell survival of UMR cells. Zoledronate concentrations of 2 μM and above dramatically reduced UMR cell proliferation. Zoledronate also selectively reduced the expression of BMP-4, while pyrophosphate selectively increased the expression of BMP-7 and FGF5, while simultaneously reducing the expression of CTGF.
Conclusions: Based on these results, zoledronate inhibits osteoblast-like UMR cell proliferation. It also inhibited transcripts of BMP4, a growth factor closely associated with bone formation. This study supports the likelihood bisphosphonates can have detrimental effects on bone formation, in addition to their previously reported negative effects on osteoclast activity. This data sheds new light on a potential mechanism underlying MRONJ.