In vitro effects of alendronate on fibroblasts of the human rotator cuff tendon

Abstract

Background: Bone mineral density of the humeral head is an independent determining factor for postoperative rotator cuff tendon healing. Bisphosphonates, which are commonly used to treat osteoporosis, have raised concerns regarding their relationships to osteonecrosis of the jaw and to atypical fracture of the femur. In view of the prevalence of rotator cuff tear in osteoporotic elderly people, it is important to determine whether bisphosphonates affect rotator cuff tendon healing. However, no studies have investigated bisphosphonates' cytotoxicity to human rotator cuff tendon fibroblasts (HRFs) or bisphosphonates' effects on rotator cuff tendon healing. The purpose of this study was to evaluate the cytotoxicity of alendronate (Ald), a bisphosphonate, and its effects on HRF wound healing. Methods: HRFs were obtained from human supraspinatus tendons, using primary cell cultures. The experimental groups were control, 0.1 μM Ald, 1 μM Ald, 10 μM Ald, and 100 μM Ald. Alendronate exposure was for 48 h, except during a cell viability analysis with durations from 1 day to 6 days. The experimental groups were evaluated for cell viability, cell cycle and cell proliferation, type of cell death, caspase activity, and wound-healing ability. Results: The following findings regarding the 100 μM Ald group contrasted with those for all the other experimental groups: a significantly lower rate of live cells (p < 0.01), a higher rate of subG1 population, a lower rate of Ki-67 positive cells, higher rates of apoptosis and necrosis, a higher number of cells with DNA fragmentation, higher caspase-3/7 activity (p < 0.001), and a higher number of caspase-3 positive staining cells. In scratch-wound healing analyses of all the experimental groups, all the wounds healed within 48 h, except in the 100 μM Ald group (p < 0.001). Conclusions: Low concentrations of alendronate appear to have little effect on HRF viability, proliferation, migration, and wound healing. However, high concentrations are significantly cytotoxic, impairing cellular proliferation, cellular migration, and wound healing in vitro.

Analysis of Uterine Morphology in Ovariectomized Rats Treated With Alendronate and Hop Extract Using Open-Soruce Software

“…Furthermore, in some tissues, a significant or near-significant decrease in Ki67 expression was seen in alendronate-treated groups, especially in the AH group. This is consistent with other research which shows that bisphosphonate therapy lowers Ki67 in different tissues (Soydan et al, 2015;Kassab, 2019;Sung et al, 2020). The association of bisphosphonate therapy with a reduced risk of postmenopausal endometrial cancer seems logical in the context of lower expression of Ki67, an indicator of cellular proliferation, however, the mechanisms behind this phenomenon are still unclear (Newcomb et al, 2015).…”

Biologically‐coupled bisphosphonate chaperones effectively deliver molecules to the site of soft tissue‐bone healing

“…27 Of note, all of these studies are of very limited relevance to the current study as the BPs included in these studies are osteoclast-inhibiting and not biologically-coupled to other molecules as is the case with OFS-3. Of some relevance to the current study, Sung et al 28 demonstrated that low dose alendronate had little effect on the viability, proliferation and wound healing capacity of human rotator cuff tendon fibroblasts in vitro. Finally, although there has been some potential risk of increased tendon injury reported to be associated with the clinical use of BPs, it is difficult to attribute this risk to the use of BPs alone.…”

The Use of Intravenous Zoledronate May Reduce Retear Rate after Rotator Cuff Repair in Older Female Patients with Osteoporosis: A First In-Human Prospective Study

“…Despite the debates on the negative effect of administering anti-osteoporotic drugs after ARCR, this study clearly demonstrated that, as a risk factor, osteoporosis can be offset by administering IV zoledronate. Although Sung et al argued that a high concentration (100 × 10 −6 M) of alendronate impaired the proliferation of fibroblasts and induced cell apoptosis in an in vitro study using human rotator cuff fibroblasts [36], the concentration in the study was 10 times higher than the therapeutic dose of alendronate sodium reported by Kum et al, such that osteoclast formation was significantly inhibited at the alendronate concentration of 10 −5 M [37]. Considering that the mean oral bioavailability of alendronate in men and women was 0.59% and 0.64%, respectively, the in vivo concentration of daily oral ingestion of 10-mg alendronate was only 0.24 × 10 −6 M. Although it appears that the injection of 5 mg of IV zoledronate with a monoisotopic mass of zoledronate at 272 g/mol induces high serum concentration, which negatively affects cells, the half-life of zoledronate is only 146 h, and it is washed out of the body.…”

“…Cancienne et al reported the low effectiveness of bisphosphonate medications in osteoporotic patients in decreasing the failure rate after ARCR. Other studies have focused on the negative effects of using bisphosphonate, including cytotoxicity, impaired cellular proliferation, cellular migration, and wound healing, which impede and negatively affect rotator cuff healing [7,35,36]. However, the data analyses in these studies are based on a national database that could be miscoded and noncoded; therefore, the results obtained from these studies can be misleading.…”