Osteoporosisis a common metabolic bone disease, affecting about 10.2 million US adults aged 50 years and older.1Patients with osteoporosis have an increased risk of vertebral compression fractures (VCFs), occurring in approximately 550,000 osteoporotic patients each year.1–3Osteoporosis occurs because of an imbalance between osteoclast activity, which is responsible for bone resorption, and osteoblast activity, leading to decreased bone mass.2Osteoporosis is diagnosed when a World Health Organization T-score of −2.5 or lower is detected on a dual-energy x-ray absorptiometry (DEXA) scan.4Furthermore, in patients requiring spinal fusion, osteoporosis may impair fusion because fusion is dependent on appropriate bone formation and remodeling.3In addition to having lower fusion rates, patients are at an increased risk of cage subsidence, screw loosening, iatrogenic fractures, and proximal junctional kyphosis.5
Osteoporosis treatments may increase fusion rates in patients with lower bone mineral density (BMD) following spinal fusion. Among these therapies, bisphosphonates constitute the broadest and oldest class of drugs, suppressing bone resorption by binding to hydroxyapatite and preventing its enzymatic cleavage.6Anabolic agents are more modern medications, with teriparatide being the most widely studied. In contrast to bisphosphonates, teriparatide exerts its action by directly stimulating surface receptors in osteoblasts to amplify bone formation.7The use of these treatments in osteoporotic patients has prompted investigation into their utility in the perioperative management of patients undergoing spinal fusion, with multiple animal studies having investigated both classes of drugs.5,8–12
Though clinical evidence supporting the use of osteoporosis therapies is expanding, there are few comprehensive meta-analyses investigating both bisphosphonates and teriparatide. While previous meta-analyses evaluating the impact of these agents on spinal fusion exist, these studies have focused heavily on the role of bisphosphonates.13–15Furthermore, there have been very few recent systematic reviews detailing the impact of teriparatide on spinal fusion rates and none with meta-analyses of the available data.16We present a comprehensive systematic review and meta-analysis of osteoporosis therapies and their impact on spinal fusion rates and offer novel findings on the utility of teriparatide in the postoperative treatment of osteoporotic patients who have undergone spinal fusion.
开云体育世界杯赔率
Inclusion and Exclusion Criteria
Studies evaluating clinical and radiological outcomes of spinal fusion in humans with osteoporosis were included in this review. The exclusion criteria were as follows: 1) studies with nonhuman cohorts; 2) studies that did not incorporate pharmacological management; 3) studies without a comparison or control group; 4) studies that did not evaluate spinal fusion outcomes; 5) studies that did not include a measurement of the fusion rate or a biomechanical, histological, radiographic, or microstructural assessment of fusion quality; 6) studies without a statistical analysis; and 7) case reports.
Literature Search and Selection
We performed a systematic search of the English-language literature dating from July 1990 to October 5, 2020, in the PubMed and Embase databases. The following medical subject heading (MeSH) terms and free text words were used: “spinal fusion” or “arthrodesis” or “spine” or “osteoporosis” or “osteoporotic.” A total of 247 published abstracts or papers were identified. As displayed in a PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flowchart (Fig. 1), after applying the inclusion and exclusion criteria, a total of 11 papers were included in the qualitative analysis and 9 in the quantitative analysis. Selection and data extraction of the studies were independently performed by two authors (V.G. and A.D.).
Study flow diagram. Data added to the PRISMA template [from Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement.PLoS Med 6(7): e1000097] under the terms of the Creative Commons Attribution License.
Data Analysis
The pooled data analysis was performed with Review Manager 5.4 (RevMan, Cochrane). Odds ratios and 95% confidence intervals were calculated using the Mantel-Haenszel test, and forest plots were generated for each comparison. Random-effects dichotomous models were developed to assess the overall effect of each drug in control and treatment groups. Our primary outcome of interest was fusion rate. Other secondary outcomes included VCF, postoperative screw loosening, postoperative BMD, postoperative Oswestry Disability Index (ODI), and postoperative visual analog scale (VAS) pain score. Risk of bias was assessed using the Cochrane risk-of-bias tool in order to give further insight into the conclusions made by us and our own subsequent meta-analyses.
Results
Study Selection and Characteristics
Eleven articles met the inclusion criteria from an initial pool of 247 articles.2,5,6,8–12,21,31,47All studies had a controlled design and evaluated fusion mass radiographically, surgically, histologically, or a combination thereof. Nine studies were included in the quantitative analysis.2,5,6,10–12,21,31,47Key differences are summarized inTable 1. Nine studies investigated bisphosphonates, 7 reviewed teriparatide, and 1 studied denosumab, a monoclonal receptor activator of nuclear factor κ B ligand (RANKL) antibody. Among the bisphosphonate studies, 5 used a negative control arm and the other 4 compared outcomes to a teriparatide treatment arm. Among the teriparatide studies, 2 had a negative control arm, 1 compared outcomes to a denosumab treatment arm, and the others compared outcomes to a bisphosphonate treatment arm. All studies evaluated fusion outcomes using CT and/or radiographs with dynamic views. All studies administered their interventions solely postoperatively except the study performed by Ide et al. (1 month preoperatively and 12 months postoperatively) and the studies performed by Ohtori et al. (treated 2 months prior in Ohtori et al., 2012 and 2013, and 3 months prior in Ohtori et al., 2015).8–11The studies by Ohtori et al. also treated patients for 8 months, 10 months, and up to 10 months postoperatively in 2012, 2013, and 2015, respectively.9–11
Summary of studies, including primary endpoints, treatment duration, and follow-up duration
| Authors & Year | Study Type | 不。of Patients | Age (yrs) | T-Score | Procedure | Intervention | Control Arm | Primary Endpoint | Treatment & FU |
|---|---|---|---|---|---|---|---|---|---|
| Nagahama et al., 20112 | RCT | 40 | >18 | 1-level PLIF | Alendronate | Vitamin D | Fusion rate | Wkly admin for 12 mos, 12 mos FU | |
| Chen et al., 201621 | RCT | 79 | >18 | ≤−2.5 | 1-level PLIF | Zoledronate | Saline | Fusion rate | Single infusion postop, 12 mos FU |
| Ebata et al., 20178 | RCT | 74 | >50 | 1-level PLIF or TLIF | Teriparatide | No medication | Fusion rate | Wkly admin for 6 mos, 6 mos FU | |
| Ide et al., 20189 | RCT | 16 | 74 ± 7 | 1-, 2-, or 3-level PLIF | Teriparatide & denosumab | Teriparatide | Fusion rate | Daily admin for 13 mos, 12 mos FU | |
| Ohtori et al, 201210 | Pros | 57 | 76.6 ± 6.9 | 1- or 2-level PLF | Teriparatide | Risedronate | Fusion rate | Daily admin for 10 mos, 12 mos FU | |
| Ohtori et al., 201311 | Pros | 62 | 77.6 ± 6.0 | 1- or 2-level PLF | Teriparatide or risedronate | No medication | Screw loosening | Daily admin for 12 mos, 12 mos FU | |
| Cho et al., 20175 | Pros | 47 | >18 | <−2.5 | 1- or 2-level PLIF | Teriparatide | Alendronate | Fusion rate | Treated at least 12 mos, 24.7 ± 2.0 mos FU (teriparatide, daily); 29.9 ± 8.1 mos FU (alendronate, wkly) |
| Kim et al., 201447 | Retro | 44 | 64.7 | 1-level LIF | Alendronate | No medication | Fusion rate | Wkly admin until FU, mean 33.8 mos FU | |
| Ohtori et al., 201512 | Retro | 45 | 71.0 ± 7.0 | 1- or 2-level PLF | Teriparatide | Risedronate | Fusion rate | Daily teriparatide (5.5 or 13 mos) or wkly risedronate (13 mos), 18 mos FU | |
| Ding et al., 20176 | Retro | 64 | >18 | TLIF, unspecified levels | Zoledronate | No medication | Fusion rate | Initial infusion then another after 12 mos, 24 mos FU | |
| Kim et al., 201831 | Retro | 84 | >18 | <−2.5 | 1-, 2-, or 3- level TLIF | Teriparatide | Risedronate | Screw loosening | Daily teriparatide for 6 mos, then 6 mos risedronate or wkly risedronate for 12 mos, 12 mos FU |
admin = administration; FU = follow-up; LIF = lumbar interbody fusion; PLF = posterior lumbar fusion; PLIF = posterior lumbar interbody fusion; Pros = prospective; RCT = randomized controlled trial; Retro = retrospective; TLIF = transforaminal lumbar interbody fusion; wkly = weekly.
Values are expressed as the mean ± standard deviation, unless indicated otherwise.
Characteristics of the intervention and control arms of the studies included in the quantitative analysis are summarized inTable 2. The numbers of intention-to-treat patients in the bisphosphonate, teriparatide, and control arms are also presented inTable 2. A risk-of-bias summary is presented inFig. 2.
Characteristics of studies included in quantitative analyses
| Authors & Year | Intervention Arm | Control Arm | ||||||
|---|---|---|---|---|---|---|---|---|
| 不。of ITT Patients | 不。Receiving Therapy* | Mean Preop BMD (femur neck/L1–4, T-score, or % YAM) | Mean Age (yrs) | 不。of ITT Patients | 不。Receiving Therapy* | Mean Preop BMD (femur neck/L1–4, T-score, or % YAM) | Mean Age (yrs) | |
| Nagahama et al., 20112 | 20 | 19 | −2.6 | 70.2 | 20 | 17 | −1.9 | 67.4 |
| Chen et al., 201621 | 40 | 33 | 0.485 ± 0.005/0.709 ± 0.003 | 65 ± 8 | 39 | 36 | 0.483 ± 0.005/0.698 ± 0.004 | 63 ± 7 |
| Ohtori et al., 201210 | 29 | 29 | 65 ± 5 | 76 ± 6.5 | 28 | 28 | 64 ± 6 | 77 ± 6.0 |
| Ohtori et al., 201311 | 40 | 40 | 66 ± 4 (teriparatide), 64 ± 4 (risedronate) | 78 ± 6.0 (teriparatide), 75 ± 5.0 (risedronate) | 22 | 22 | 64 ± 6 | 77 ± 5.8 |
| Cho et al., 20175 | 23 | 23 | −3.7 ± 0.6 | 71.0 ± 4.9 | 24 | 24 | −3.5 ± 0.6 | 68.2 ± 8.4 |
| Kim et al., 201447 | 21 | 21 | −3.75 | NA | 23 | 23 | −3.98 | NA |
| Ohtori et al., 201512 | 30 | 30 | 65.6 ± 6 (long), 63.0 ± 7.8 (short) | 72 ± 7.7 (long), 69 ± 7.1 (short) | 15 | 15 | 66.8 ± 8.0 | 71 ± 6.0 |
| Ding et al., 20176 | 30 | 30 | NA | 64.53 ± 6.86 | 34 | 34 | NA | 66.44±6.44 |
| Kim et al., 201831 | 33 | 33 | −3.09 ± 0.49 | 69.48 ± 7.76 | 51 | 51 | −2.94 ± 0.39 | 66.75 ± 6.46 |
ITT = intention to treat; long = long duration; NA = not available; short = short duration; YAM = young adult mean.
Values are expressed as the mean ± standard deviation, unless indicated otherwise.
Risk-of-bias summary for included studies.Green plusdenotes low risk of bias.Red minusdenotes high risk of bias.Empty celldenotes unclear risk.
Fusion Rates
Fusion rates in most studies were reported as the number of fused index levels per total index levels assessed. Among the bisphosphonate versus negative control studies, 3 reported fusion rates at 6 months and 4 reported rates at 12 months postoperatively. Of the 102 levels that underwent fusion surgery in the bisphosphonate treatment arm and were evaluated for successful fusion at 6 months, 83 (81.4%) met grade A or B fusion criteria based on the Bridwell system17for either bilateral or unilateral bridging bone formation, respectively. In the control arm at 6 months, 65 (59.6%) of 109 levels met fusion criteria. At 12 months, 105 (85.4%) of 123 levels in the bisphosphonate treatment arm and 110 (83.3%) of 132 levels in the control arm met fusion criteria. A Cochran-Mantel-Haenszel test demonstrated higher odds of successful fusion among patients taking bisphosphonates versus unmedicated controls at 6 months postoperatively (OR 3.33, 95% CI 1.72–6.42, p = 0.0003) but not at 12 months postoperatively (OR 1.14, 95% CI 0.47–2.79, p = 0.77;Fig. 3AandB）.This suggests that bisphosphonate therapy might increase the rate of fusion only during the initial postoperative period (≤ 6 months) and not the long term.
Impact of medical therapy on fusion rates at 6 (A) and 12 (B and C) months postoperatively.A:Patients undergoing postoperative bisphosphonate therapy were 3.33 times more likely to experience successful fusion at 6 months relative to patients who did not receive postoperative bisphosphonate treatment (OR 3.33, 95% CI 1.72–6.42, p = 0.0003).B:Patients undergoing postoperative bisphosphonate therapy did not experience any difference in fusion rates at 12 months postoperatively as compared to patients without bisphosphonate treatment (OR 1.14, 95% CI 0.47–2.79, p = 0.77).C:Patients receiving postoperative teriparatide therapy were 2.05 times more likely to experience successful fusion relative to patients who received postoperative bisphosphonate therapy (OR 2.05, 95% CI 1.17–3.59, p = 0.01).
Among the bisphosphonate versus teriparatide studies, 3 reported outcomes at 12 months and only 1 reported outcomes at 6 months. At 12 months, 122 (83.0%) of 147 levels in the teriparatide treatment arm and 103 (70.5%) of 146 levels in the bisphosphonate treatment arm met fusion criteria. When pooled, patients in the teriparatide treatment arm had significantly higher odds of successful fusion relative to bisphosphonate patients at 12 months (OR 2.05, 95% CI 1.17–3.59, p = 0.01;Fig. 3C）.Although meta-analysis was not possible for outcomes at 6 months, Cho et al. demonstrated higher fusion rates in teriparatide patients relative to those in bisphosphonate patients at 6 months.5In a prospective study of 47 patients, they observed that 21 (77.8%) of 27 levels in the teriparatide treatment arm and 15 (53.6%) of 28 levels in the bisphosphonate treatment arm met fusion criteria.
Among the studies investigating teriparatide, only one compared fusion rates with a negative control.7Among 75 osteoporotic patients who had undergone fusion surgery, those in the teriparatide group experienced significantly higher rates of bilateral bridging bone formation relative to rates in controls at 6 months (69% vs 35.1%, p = 0.013).
VCF and Pedicle Screw Loosening
While investigators were unable to demonstrate long-term differences in the fusion rate between bisphosphonates and control, several studies reported improvement in secondary outcomes. For example, Nagahama et al. and Chen et al. reported significantly lower rates of VCF in patients receiving risedronate treatment.2,21A meta-analysis of these studies on the incidence of postoperative VCF demonstrated that patients receiving bisphosphonates were less likely to experience VCF than were patients who did not undergo bisphosphonate therapy (OR 0.07, 95% CI 0.01–0.59, p = 0.01) as shown inFig. 4C. Bisphosphonates have also been shown to limit cage subsidence and pedicle screw loosening.3,4
Impact of medical therapy on postoperative screw loosening.A:No significant differences in rates of cases with screw loosening among patients receiving postoperative bisphosphonate versus controls (OR 0.35, 95% CI 0.03–4.23, p = 0.41).B:No significant differences in rates of cases with screw loosening between teriparatide and bisphosphonates was detected (OR 0.61, 95% CI 0.27–1.37, p = 0.23).C:Summary of bisphosphonates’ impact on rates of postoperative VCF. Patients who received postoperative bisphosphonate therapy demonstrated significantly lower rates of postoperative VCF than the patients who did not receive postoperative bisphosphonate therapy (OR 0.07, 95% CI 0.01–0.59, p = 0.01).
Several studies have also measured the efficacy of medical therapy in reducing screw loosening. Most studies have reported the screw loosening incidence as the number of patients with radiographic evidence regardless of the number of fusion levels. Two studies among those investigating bisphosphonates versus a negative control and 3 studies among those investigating teriparatide versus bisphosphonate therapy reported screw loosening (Fig. 4AandB）.螺杆的速度没有显著差异loosening were observed between bisphosphonate therapy and negative controls (OR 0.35, 95% CI 0.03–4.23, p = 0.41) or between teriparatide therapy and bisphosphonate therapy (OR 0.61, 95% CI 0.27–1.37, p = 0.23).
BMD
BMD assessments at preoperative and postoperative time points were made in 2 studies that compared teriparatide versus bisphosphonate therapy (Fig. 5）.BMD measurements in these studies were obtained from the femur neck using DEXA preoperatively and at the 1-year follow-up. No significant difference in BMD scores at the 1-year follow-up was observed between the two therapies (mean difference [MD] = 0.24, 95% CI −0.02 to 0.50, p = 0.07).
Impact of postoperative medical therapy on BMD in osteoporotic patients who underwent spinal fusion. No significant difference in mean BMD T-scores was observed between teriparatide and bisphosphonate therapy (MD = 0.24, 95% CI −0.02 to 0.50, p = 0.07).
Clinical Outcomes: ODI and VAS
The ODI and VAS scores were commonly reported scores for measuring clinical outcomes. Meta-analysis of mean ODI scores from 3 studies comparing bisphosphonate versus a negative control demonstrated that bisphosphonate therapy is significantly associated with a lower mean ODI score than that in controls (MD = −2.19, 95% CI −2.94 to −1.44, p < 0.00001;Fig. 6A）.当比bisph teriparatide治疗osphonate therapy, teriparatide patients demonstrated a nonsignificant decrease in ODI scores (MD = −1.74, 95% CI −3.74 to 0.27, p = 0.09;Fig. 6B）.Mean VAS scores were also significantly lower in the bisphosphonate therapy group relative to those in negative controls (MD = −0.58, 95% CI −0.79 to −0.38, p < 0.00001;Fig. 6C）.In contrast to ODI scores, VAS scores were significantly lower among patients taking teriparatide therapy than among those in the bisphosphonate arm (MD = −0.35, 95% CI −0.64 to −0.05, p = 0.02;Fig. 6D）.
Impact of medical therapy on ODI and VAS scores.A:Patients undergoing postoperative bisphosphonate therapy had significantly lower ODI scores following bisphosphonate therapy (MD = −2.19, 95% CI −2.94 to −1.44, p < 0.00001).B:Patients undergoing postoperative teriparatide therapy did not experience significantly lower ODI scores relative to those in patients who did not undergo postoperative teriparatide therapy (MD = −1.74, 95% CI −3.74 to 0.27, p = 0.09).C:Patients undergoing postoperative bisphosphonate therapy had significantly lower VAS scores (MD = −0.58, 95% CI −0.79 to −0.38, p < 0.00001).D:Patients undergoing postoperative teriparatide therapy had significantly lower VAS scores (MD = −0.35, 95% CI −0.64 to −0.05, p = 0.02).
Metabolic Markers
In a retrospective study exploring fusion outcomes with zoledronate, Ding et al. measured the bone metabolic markers carboxy-terminal cross-linked telopeptide of type I collagen (β-CTX) and amino-terminal propeptide of type 1 procollagen (P1NP) at 10 days and at 3-month intervals up to 12 months postoperatively.6Both markers were significantly suppressed in the zoledronate group at all time points (p < 0.05), which indicates decreased bone resorption. Ebata et al., in a randomized controlled trial assessing fusion outcomes with teriparatide therapy, also measured the serum concentrations of P1NP and tartrate-resistant acid phosphatase 5b (TRACP-5b) as biomarkers of bone formation and bone resorption, respectively.8At 1 month postoperatively, patients in the teriparatide arm had a significantly higher serum concentration of P1NP (p < 0.012) and a significantly lower serum concentration of TRACP-5b at 6 months (p < 0.001). The authors also measured serum concentrations of alkaline phosphatase, a marker of bone formation, in their patient cohort. In the patients who received teriparatide alone, serum alkaline phosphatase concentrations were significantly higher 3 months postoperatively (p < 0.05).
Discussion
The increasing prevalence of osteoporosis and spine procedures has prompted interest in the utility of adjuvant medications in improving successful postoperative fusion. Currently, the two most prevalent treatment classes for decreased BMD are bisphosphonates, which inhibit the enzymatic cleavage of hydroxyapatite, and teriparatide, which directly stimulates osteoblasts to augment bone formation.14,15However, the current level of evidence regarding the utility of these drug classes remains unclear, with the most recent systematic reviews on the subject lacking objective assessment of these agents’ utility.16,18,19In addition, short-term versus long-term effects of these medical therapies on fusion remain unclear.
Fusion Rates
Nine studies explored fusion rates in osteoporotic patients treated with medical therapy. Five of these compared bisphosphonate outcomes to negative controls,2,6,13,20,211 compared teriparatide to negative controls,8and 3 compared teriparatide to bisphosphonates.5,10,12
磷酸盐在患者的使用spinal fusion surgery has been a source of debate. Prior animal studies have demonstrated that bisphosphonates may negatively modulate spinal fusion by inhibiting osteoclast activity and, subsequently, bone remodeling.22–25In a prospective study comparing bone fusion rates in patients taking long-term bisphosphonates (≥ 2 years) and nonusers, Kang et al. found that long-term bisphosphonate users had significant delayed union 6 months after fusion relative to that in nonusers (26% vs 42%, respectively; p < 0.05).26然而,在长期随访没有significant differences in fusion rates were observed. The authors postulated that bisphosphonates delay bone callus maturation rather than inhibit fusion, which may explain the delay in fusion seen in the alendronate group. Conversely, in a retrospective review of patients who received a single dose of zoledronate after posterolateral fusion, Park et al. demonstrated no significant decrease in fusion mass in patients who had received zoledronate.27
In all studies that explored the effects of bisphosphonate therapy on lumbar spinal fusion rates in patients with osteoporosis at 6 months or less, bisphosphonates accelerated the fusion process.2,6,21At 12 months, these differences were nonsignificant. Our group analyses confirmed these observations by demonstrating higher odds of successful fusion at 6 months (OR 3.33, p = 0.0003) but not at 12 months (OR 1.14, p = 0.77).
In contrast to bisphosphonates, teriparatide administration has enhanced spinal fusion in various animal models.28–30In a multicenter, prospective randomized controlled trial, Ebata et al. explored the role of once-weekly teriparatide therapy in osteoporotic women after fusion surgery.8They observed that teriparatide treatment significantly enhanced rates of complete fusion at 6 months relative to rates in the control arm (69% vs 35%, p = 0.013). To our knowledge, long-term studies exploring fusion rates at 12 months in patients taking teriparatide versus negative controls have not been reported.
With both teriparatide and bisphosphonates having clear benefits in enhancing spinal fusion during the short-term postoperative period and a clear difference in the cost of treatment, determining differences in outcomes is important. All 3 studies that explored fusion rates between teriparatide and bisphosphonates demonstrated significantly higher rates of complete spinal fusion in the long term among the teriparatide-treated patients.5,10,12This finding was confirmed in our group analysis, which demonstrated an OR of 2.05 (p = 0.01) for successful fusion in favor of teriparatide. Cho et al. also demonstrated a superior rate of complete fusion at 6 months in the teriparatide group (78% vs 54%).
Lastly, supplementation of teriparatide with denosumab may also improve fusion rates. In a randomized controlled trial investigating the daily use of 20 µg of subcutaneous teriparatide therapy alone versus supplementation with 60 mg of denosumab every 6 months after fusion, Ide et al. demonstrated bone union rates of 82% and 91% at 6 and 12 months, respectively, in the combination therapy arm versus 36% and 64% in the teriparatide-alone arm.9In addition, teriparatide’s potent anabolic effects on bone remodeling and ability to preferentially activate osteoblasts has shown a significantly higher degree of improvement in BMD long-term (≥ 12 months) relative to that with bisphosphonates.5,9,31
Bone Quality
关于二磷酸盐的作用s in increasing bone quality, multiple studies have demonstrated the ability of bisphosphonates to prevent VCFs and screw loosening.32,33In a prospective randomized controlled trial with 2027 women with osteoporosis and preexisting vertebral fractures, Black et al. demonstrated a significant reduction in subsequent VCFs among patients in the alendronate group (8%) relative to those in the control group (15%).34Our meta-analysis confirms this finding as well. Therefore, although bisphosphonates may not be the optimal therapy for augmenting fusion rates, they may have a role in preventing pathological changes, such as VCFs, and reducing postoperative pain and disability in osteoporotic patients undergoing spinal fusion.2,6,21Currently, animal models have demonstrated that zoledronate and teriparatide synergistically accelerate fusion mass and bone deposition.35
Denosumab, a monoclonal antibody that has been used as a fracture prophylactic in postmenopausal osteoporotic females, is another potential therapy.19It exerts its protective effects by binding to and inactivating RANKL.9排名L has been demonstrated to increase osteoclast proliferation and activity, and the reduction of estrogen in older females has been shown to increase tissue exposure to RANKL, stimulating bone resorption.36Two long-term randomized controlled clinical trials (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months [FREEDOM]) have shown that denosumab significantly reduces bone turnover markers, reduces fracture rates, and demonstrates low rates of adverse events.37,38More studies investigating the impact of denosumab following spinal fusion are necessary to determine its clinical value and structural impact.
In contrast to bisphosphonates and denosumab, teriparatide has demonstrated anabolic effects by directly accelerating bone formation and fracture healing in multiple clinical studies, including in vertebral fractures.39–41此外,eff teriparatide已被证明ective in short-term administrations, with fusion mass acceleration being demonstrated with treatment durations as short as 8 weeks.13,42,43However, the results of our meta-analyses demonstrate that teriparatide has limited benefit in improving secondary outcomes such as postoperative pain and disability. Larger prospective trials are still needed to elucidate the true effect on clinical outcomes.
Clinical Outcomes
Clinical outcomes, as measured by ODI and VAS scores, were better in nearly all therapy groups relative to those in controls. When ODI and VAS scores were pooled, we observed that the bisphosphonate treatment was significantly associated with lower mean ODI and VAS scores relative to those in negative controls. This was in contrast to scores in the teriparatide group compared to those in a negative control group among the 3 studies included in our review.7,8,11Although teriparatide is known to reduce back pain,44no differences in pain or ODI scores were observed between teriparatide and controls. Similarly, in the studies that compared teriparatide therapy with bisphosphonates as a control, no statistical difference in ODI scores between the two groups was observed.10,11,31However, mean VAS scores were significantly lower in the teriparatide group.
The results of our meta-analysis suggest that postoperative teriparatide treatment may be beneficial in accelerating and promoting fusion in osteoporotic patients. Likewise, our findings suggest that teriparatide is superior to bisphosphonates in increasing fusion rates and is associated with lower postoperative VAS scores in osteoporotic patients. However, more studies comparing patients who received postoperative teriparatide to unmedicated patients are necessary. On the basis of our analysis, we believe that teriparatide offers a superior option for rapid and complete spinal fusion relative to bisphosphonates and suggest that teriparatide be utilized immediately after surgery barring any contraindications.
Lastly, it is well known that teriparatide is costly and that some insurance companies may not cover its cost. Although a cost-benefit analysis has not been previously reported, we believe that the elevated cost of teriparatide is offset by the significantly higher rates of complete fusion associated with its use. Lower rates of fusion may expose patients to pathological fractures or revision surgery for pseudarthrosis, thus increasing long-term costs and morbidity.45,46Physicians should assess which patients require a more aggressive course of biologics preoperatively (e.g., patients with more severe pathology based on a history of prior fracture and/or BMD scores) and the patient’s insurance provider and prescribe treatment accordingly. Also, the assessment for teriparatide candidacy should begin prior to surgery, as the insurance approval process may be lengthy.
There may also be benefits to preoperative treatment with teriparatide, as shown by Ohtori and colleagues.10–12然而,没有一个直接的比较融合老鼠es in patients who received both pre- and postoperative therapy versus postoperative teriparatide alone, no firm conclusions can be made. However, the cost-effectiveness of teriparatide may be increased if it can be shown that fusion rates do not significantly differ between pre- and postoperative teriparatide regimens.
Study Limitations
One limitation of this work was the lack of clinical studies evaluating fusion rates in teriparatide groups relative to those in unmedicated groups. While the results of the randomized controlled trials are promising, more studies comparing teriparatide-treated patients with unmedicated patients would reinforce the utility of postoperative teriparatide use. Another limitation of this review is the variation in the fusion grading systems used in several studies. Ohtori et al. graded fusion using the Bridwell system, whereas Cho et al. used the Ito system. Another Ohtori study did not reference a specific fusion grading system.3,10,12The behavior of patients undergoing long-term bisphosphonate therapy is also unknown. There are also significant variations in the dosages, treatment patterns, and study designs of the various included studies. Lastly, our risk-of-bias assessment revealed that 2 of our studies did not employ randomization, 3 did not adequately blind evaluators, and 1 study disproportionately experienced dropout in its treatment arm.5,6,8,10,31,47The lack of randomization in the prospective Cho and Ohtori studies is particularly concerning, as any systematic differences between their treatment and control groups could lead to erroneous conclusions.
Conclusions
Our systematic review and meta-analysis demonstrate the benefit of bisphosphonates in accelerating fusion during a short-term monitoring period of 6 months. We also show that teriparatide is likely an optimal postoperative therapy for accelerated bone healing at long-term periods following spinal fusion in osteoporotic patients because of its rapid anabolic effects. Furthermore, while bisphosphonates have been a mainstay in osteoporosis treatment, their mechanism of action and lack of efficacy in improving long-term fusion rates may restrict their role to reducing the risk of VCFs and limiting postoperative pain and disability. Similarly, denosumab may only serve a prophylactic role, but more studies are required to evaluate its utility.
Disclosures
Dr. Wang owns stock in Innovative Surgical Devices, Medical Device Partners, Spinicity, and Kinesiometrics; is a consultant for K2M, Spineology, Stryker Spine, DePuy-Synthes Spine, and Medtronic; holds a patent with DePuy-Synthes Spine; receives royalty payments from DePuy-Synthes Spine, Children’s Hospital of Los Angeles, Springer Publishing, and Quality Medical Publishing; receives grants from the Department of Defense; and is an advisory board member for Vallum. Dr. Levi receives teaching honoraria from the American Association of Neurological Surgeons and Medtronic and grant support from the Department of Defense and the National Institutes of Health (NIH-NINDS).
Author Contributions
Conception and design: Levi, Perez-Roman, Burks. Acquisition of data: Govindarajan, Diaz. Analysis and interpretation of data: Govindarajan, Diaz. Drafting the article: Govindarajan, Diaz, Perez-Roman. Critically revising the article: Perez-Roman, Burks, Wang. Reviewed submitted version of manuscript: Levi, Perez-Roman, Burks, Wang. Approved the final version of the manuscript on behalf of all authors: Levi. Statistical analysis: Govindarajan. Administrative/technical/material support: Levi. Study supervision: Levi.
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5 ↑
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6 ↑
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7 ↑
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8 ↑
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9 ↑
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10 ↑
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11 ↑
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12 ↑
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13 ↑
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14 ↑
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16 ↑
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17 ↑
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18 ↑
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20 ↑
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21 ↑
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26 ↑
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27 ↑
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31 ↑
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32 ↑
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33 ↑
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35 ↑
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37 ↑
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42 ↑
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46 ↑
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47 ↑
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