Despite great progress in implant design, materials and new implantation techniques aseptic loosening is still the most frequent cause of implant failure in THA, which was found to be increased especially in patients with osteonecrosis of the femoral head (ON-FH). While a direct link between aseptic loosening and periprosthetic bone loss still remains elusive, there is plentiful evidence for a close association with early migration of implant components. Although the beneficial effect of bisphonates on periprosthetic bone mass is well established, little is known to date about their effects on implant migration. This is an important issue, because successful prevention of early implant migration would provide strong evidence of a beneficial effect on the survival rate of THA. Previously, Krismer et al. found that a total migration of the cup of ≥ 1mm and a subsidence of ≥ 1.5mm 2 years after surgery was highly predictive for aseptic implant failure of THA within 8 to 10 years.

Fifty patients with end-stage ON-FH were consecutively enrolled to receive either 4mg of ZOL or saline solution (CTR) in a double-blind fashion. Radiographs standardized for EBRA-digital analysis were performed at each follow-up exam at 7 weeks, 6 months, 1 year, and yearly thereafter. The minimum follow-up period was 2 years (median follow-up: 2.8 years). Migration of the acetabular and femoral components was analyzed with the EBRA-digital software (University of Inns-bruck, Austria) independently by 3 investigators fully blinded to randomization.

Within the placebo group, distal migration of the stem (subsidence) steadily increased up to −1.2mm ± 0.6 SD at 2 years after THA without reaching a plateau phase (P< 0.001, Friedman ANOVA). Less but a nearly curvilinear migration pattern was found for the acetabular components, with a transverse migration of 0.6mm ± 1.0 SD and a vertical migration of 0.6mm ± 0.8 SD at 2 years (P< 0.001, Friedman ANOVA). Treatment with ZOL effectively minimized the migration of cups in both the transverse and vertical direction (0.15 mm ± 0.6 SD and 0.06 mm ± 0.6 SD, respectively, P< 0.05, ANOVA), and a trend to a decreased subsidence was also found for stem migration (−0.91 mm ± 0.51 SD; P=0.11, ANOVA). In addition, total cup migration exceeding 1mm at 2 years was significantly reduced by ZOL in 8 patients (12 vs 4 in CTR vs ZOL, respectively) as was also found in 6 patients for subsidence (≥ 1.5mm in 9 vs 3 patients in CTR vs ZOL, respectively) (P< 0.05, Fisher’s exact).

This is the first clinical trial reporting that a single infusion of ZOL suffices to improve initial implant fixation in THA. Based on best evidence available to date, this new concept shows great promise of improving the long-term outcome in THA and should be given attention in long-term trial.

Background: Aseptic loosening of implants is commonly associated with periprosthetic bone loss, and several authors aimed to preserve periprosthetic bone mass by treatment with bisphosphonates (BPs) in THA. While local application of BPs was argued to provide higher concentrations of bioactive drug at the component-bone interface, we hypothesized that a systemically administration of BPs will be sufficient for sustained effects on local bone metabolism due to local accumulation of the drug in freshly exposed bone mineral early after reaming during implantation. The high antiresorptive potential of zoldronic acid (ZOL) on osteoclasts will be sustained locally by re-attachment after release by osteoclast resorption during the remodelling cycle. While we were able to demonstrate beneficial effects of ZOL on early implant fixation, its local effects on bone metabolism is best reflected by monitoring the relative changes of biochemical markers during follow-up after THA. This is an important issue to be addressed, since there are no reliable data available but essential for a prove-of-concept.

Methods: Fifty patients with ON-FH were consecutively enrolled to receive randomly either 4mg of ZOL or saline solution (CTR) in a double-blind fashion one day after THA. The biochemical bone turnover markers C-terminal teleopeptides of collagen type I (ICTP), CrossLaps (CL), osteocalcin (OC), osteoprotegerin (OPG), soluble RANKL, as well as 25-hydroxyvitamin D (25OHD3) were measured from fasting blood samples before surgery and at 7 weeks, 6 months, 1 year, and yearly thereafter. One patient was lost and after excluding three patients with deficiency in renal function 22 and 24 patients were analyzed in ZOL and CTR, respectively, during a median follow-up of 2.8 yrs.

Results: Within the placebo group, the bone resorption markers ICTP and CL peaked at 7 wks, but continuously decreased thereafter beyond baseline levels. The bone formation marker OC also increased, but peaked at 6 months and stayed increased during the follow-up. Although there was only a transient effect of ZOL found in ICTP, CL rapidly decreased within 7 wks and remained depressed during the whole follow-up period (~ − 65% at 2 yrs, P< 0.0001). Similarly, OC was also depressed in ZOL but never reached significance compared to baseline levels (~ − 19%, NS). No differences or changes were apparent in 25OHD3 levels.

Discussion and Conclusion: The findings strongly support a predominant local effect of systemically infused ZOL over a whole-body effect. Furthermore, the data demonstrate the sufficiency of a single infusion of a single infusion of ZOL for a pronounced and sustained antiresorptive effect after THA, which is essential to preserve periprosthetic bone mass in an effort to prevent aseptic loosening.

The ability of hMSCs to differentiate into several mesenchymal cell lineages including the osteoblast lineage plays a key role in skeletogenesis and bone regeneration. Although the importance of physical factors in the development and maintenance of bone tissue has been recognized for many years and we previously demonstrated that mechanical strain constitutes an inherent stimulus for osteogenic differentiation of undifferentiated hMSCs, there is strong evidence to suggest that obesity is an independent factor in the risk of implant failure due to aseptic loosening or fracture after TJR. While mechanical complications and overload have been widely suggested, we hypothesized that the osteogenic mechanoresponse of hMSCs may be profoundly altered in obese patients.

hMSCs were isolated from bone marrow of 10 donors (BMI ranging from 18.7 to 37.6 kg/m2). The individual response of unidfferentiated hMSCs to cyclic tensile strain (CTS) was determined in a two-armed study design (strained versus unstrained (CTR)) using a 4-point bending device, where strain was restricted to a maximum of 3,000 μstrain. Phenotypic effects were characterized by analyzing cell numbers, cell viability and ALP activity; mRNA levels of marker genes related to early osteogenic differentiation (RUNX2, ALPL, SPARC, SPP1), protein synthesis (COL1A1), and cell cycle (MKI67) were determined by real-time RT-PCR. Possible contributions to anthropomorphometric variables and individual triglycerides, cholesterin, glucose, leptin, adiponectin, resistin, and estradiol levels were evaluated by linear regression analysis.

We found a significant up-regulation of the osteogenic marker genes due to CTS, including RUNX2 (1.9 fold), ALPL (2.4 fold), SPP1 (2.8 fold), and SPARC (4.1 fold), which was accompanied by an increase in cell-based ALP activity from 6.1 ± 1.2 μM/min/106 in CTR to 8.5 ± 1.7 μM/min/106 in CTS (plus 39.6 ± 9.8% SEM, P< 0.05). Cell density was significantly lower following CTS (minus 20.0 ± 4.7%, P< 0.05), which was also found for cell viability (XTT minus 17.8 ± 5.6%, P< 0.05). As a consequence, the phenotypic CTS response (ALP activity w/o normalization) ranged widely between donors (−30.8% to +60.1%) and was highly significant inverse correlated to donor’s BMI (r= −0.91, P< 0.0001). Additionally, leptin and estradiol levels determined within bone marrow plasma were significantly correlated with the phenotypic mechanoresponse (r=−0.71, P=0.028, and r=0.67; P=0.039; respectively).

The findings demonstrate that the osteogenic mechanosensitivity of hMSCs is highly affected by physiological factors related to donor’s BMI. Such an upstream imprinting process within bone marrow may be an important area of further research, since obesity-linked problems constitute increasing concerns in orthopaedic surgery within the western world.

The induction of differentiation is a highly programmed lineage-specific process and several studies have provided great insight into the microenvironment affecting differentiation of multipotential hMSCs. In this regard, the importance of physical factors has been recognized for many years, but only little is known about its effects on undifferentiated hMSCs. The study aimed to determine the early osteogenic differentiation response to physiologically-based mechanical tensile strain with possible contributions to donor-specific physiological conditions.

MSCs of ten donors were expanded under standard culture conditions, and the individual response to cyclic tensile strain (CTS) was determined in a two-armed study design (strained versus unstrained (CTR)). CTS was applied with a maximum of 3,000 μstrain. Genotypic characteristics (RUNX2, ALPL, SPARC, SPP1; COL1A1, MKI67, etc) as well as phenotypic effects (cell numbers, cell viability and ALP activity) were compared between CTR and CTS, and possible relations to donor-specific physiological characteristics including anthropomorphometric and biochemical variables were determined.

We found a significant up-regulation of the osteogenic marker genes due to CTS, which was accompanied by an increase in cell-based ALP activity (plus 39.6 ± 9.8% SEM, P< 0.05). Cell density as well as XTT were significantly lower following CTS (minus 20.0 ± 4.7% and minus 17.8 ± 5.6%, respectively, P< 0.05). As a consequence, the ALP activity w/o normalization ranged widely from minus 30.8% to plus 60.1% between individual donors and was a function of donor’s BMI (r=−0.91, P< 0.0001), weight (r=−0.73, P=0.016), and age (r=−0.65, P=0.041).

The findings demonstrate that

the application of CTS provides an inherent osteogenic differentiation stimulus for undifferentiated hMSCs in vitro, and

Aseptic loosening is the most frequent cause of implant failure in total hip arthroplasty (THA). Additionally, failure rate was still found by some authors to be increased in patients with osteonecrosis of the femoral head (ON-FH). It is well evidenced that low initial fixation and early migration precedes and predicts long-term failure rate of both, the acetabular and femoral component in THA.

This independent, double-blind, randomized, controlled study was primarily designed to evaluate whether a single infusion of 4 mg of zoledronic acid is sufficient to prevent implant migration determined by the EBRA-digital method. Fifty patients were consecutively enrolled between July 2002 and March 2005 to receive either 4 mg zoledronic acid (ZOL) or saline solution (CTR) one day after THA (Zweymüller system, cementless). Plain radiographs were performed postoperatively and all parameters were evaluated at each follow-up meeting interval at 7 weeks, 6 months, 1 year, and yearly thereafter during a median follow-up period of 2.8 years (2 years minimum).

In CTR, subsidence increased up to −1.2 mm ± 0.6 SD at 2 years in CTR (P< 0.001). Less, but a near curve-linear shaped migration pattern was found for the ace-tabular component, with an averaged medialization of 0.6 mm ± 1.0 SD and a cranialization of 0.6 mm ± 0.8 SD at 2 years (P< 0.05, Friedman ANOVA) at 2 years. In ZOL, a significant reduction in bone turnover markers was accompanied by a complete prevention of cup migration in both, the transverse and vertical direction (P< 0.05, ANOVA), while there was only a trend to a decreased subsidence in stems.

The study provides useful data which are promising and support the suggestions that bisphosphonates may offer significant opportunities to reduce and prevent implant migration of THA, thus increasing long-term durability of THA especially in selected high-risk patients.