USE OF TERIPARATIDE IN SURGICAL PLANNING FOR PATIENTS WITH OSTEOPOROSIS

ABSTRACT Currently, there are no guidelines for treating osteoporosis in spinal surgery. The rate of complications such as screw loosening, proximal junction kyphosis, cage subsidence, and loss of reduction in fractures is high. Objective: To evaluate the use of teriparatide and denosumab in planning spinal surgery in an osteoporotic patient with degenerative pathology, emphasizing the fusion rate, bone mineral density, and decreased complications. Method: A systematic search was performed in medical reference databases for comparative studies of teriparatide and denosumab in spinal surgery to evaluate fusion, screw loosening, bone mineral density, and decrease in the incidence of vertebral fractures. χ2 was implemented for the statistical analysis, according to PRISMA (2020). Result: Fusion rate with teriparatide was 79.28% in the first six months, 95% CI (OR 2.62) and decreased screw loosening rate 81.9% 95% CI (OR 0.6). Increase in bone mineral density 15.5% OR 1.49 (0.77 - 2.86) and decrease in vertebral fracture rate 85.4% OR 0.5. Conclusions: Teriparatide and denosumab should be considered in perioperative spinal planning due to their effectiveness, synergism, and low adverse effects; to improve bone mineral density and decrease the rate of complications. Clinical, comparative, and statistically significant studies are required to confirm this. Level of Evidence II; Systematic Review and Meta-analysis.


INTRODUCTION
Osteoporosis is currently considered a public health problem, affecting 200 million people worldwide, 1 10% of the population in the United States, and 50 million over 50 years of age. 2,3he interest in its diagnosis and treatment has become more relevant in the last 20 years due to increased life expectancy. 4][5][6][7] Recently, the measurement of Hounsfield Units by tomography predicts outcome and post-surgical complications in planning, thus improving the success rate and greater sensitivity and specificity in diagnosing degenerative spinal pathology, scoliosis, and aortic calcification concerning DEXA. 7Only 44% of surgeons perform screening before surgery for suspected osteoporosis, and with the diagnosis, only 40% of patients receive pharmacological management. 2 Several strategies optimize the osteoporotic patient in planning, such as cementation, fenestrated screws, and drugs; however, there is no universally accepted guide to determine the best medicine, dosage, and administration time. 6ifferent drugs are used in the management.Calcium and vitamin D are inexpensive, with few adverse effects but no effect on bone mineral density and fracture risk. 3eriparatide and bisphosphonates have been the most studied drugs in spinal instrumentation.The former, a parathyroid hormone analog, has shown similar fusion but faster (77% vs. 55% six months after) with a decrease in screw loosening compared to bisphosphonates. 1,2,8,9On the other hand, bisphosphonates present greater adverse effects, such as atypical fractures of the femur, and maxillary necrosis, among others 4. Calcitonin is a regulator of calcium levels.However, it has been associated with cancer 4.6%, and studies are lacking. 3enosumab is a monoclonal antibody considered antiresorptive with promising results in spinal fusion; however, clinical studies on the spine are still lacking.It has been found to have a synergistic effect with teriparatide in enhancing the fusion rate.][11] Loosening decreases the fusion rate; therefore, it is necessary to improve the bone-implant interface in pharmacological management in cooperation with the endocrinologist 12 and to perform initial studies of alkaline phosphatase, calcium, vitamin D, and parathormone before starting teriparatide. 12ur presentation aims to evaluate and describe the different uses teriparatide and denosumab in the peri-operative planning of the osteoporotic patient with spinal pathology to determine their effectiveness in emphasizing fusion rate, bone mineral density, and decreased complications.

MATERIALS AND METHOD
TYPE OF STUDY: SYSTEMATIC REVIEW and METHOD ANALY-SIS, according to "Preferred Reporting Items" (PRISMA 2020).

Data sources and search
A systematic literature search of PubMed, Cochrane, LILACS, and Scielo databases with the MeSH terms: (osteoporosis AND Spine surgery) AND (teriparatide OR denosumab), in English language, results by year, text availability, article attribute, article type, publication date, between January 1990 and March 2022.

Eligibility criteria
Analytical studies, randomized clinical trials, systematic reviews, and meta-analyses were selected within the inclusion criteria; osteoporosis in the context of degenerative spinal pathology (BMD <-2.5 SD by bone DXA or <100 Hounsfield Units by CT scan), articles that compared the use of Teriparatide and/or Denosumab in patients with osteoporosis taken to spinal surgery and finally those that provided a recommendation.

Exclusion criteria
Descriptive articles, case series, letters, laboratory studies without patient data, duplicated, unpublished, and not performed in humans were excluded.Likewise, patients with tumor, infectious and inflammatory pathology.

RESULTS
The initial search showed 231 articles from 1990 to 2022 in Pubmed.On further screening in Pubmed, 204 articles presented full text from 2012 to 2022, of which 140 were in human and English.Forty-seven studies are obtained, and a second review is performed after reading the titles and abstracts, articles associated with rheumatoid arthritis, chronic kidney disease, osteoporosis in postmenopausal women not related to the spine, glucocorticoid osteoporosis, atypical long bone fractures, denosumab in renal transplantation for a total of 24 articles.
After the second review, 14 articles met the inclusion criteria.(Figure 1) All the 14 articles selected performed a pharmacologic comparison between teriparatide and a control group of bisphosphonates.(Table 1) Eleven studies related to fusion, of which 6 compared it at six months, four at 12 months, and 1 article at 24 months.Five articles evaluated the rate of screw loosening with pharmacological use, 1 article evaluated torque, three evaluated bone mineral density at 12 months with pharmacological management, and 2 described the presentation of vertebral fractures in osteoporotic patients older than 75 years.
Four tables were made, and using a χ 2 test, the fusion rate, screw loosening in spinal instrumentation, increase in bone mineral density, and decrease in vertebral fractures (in patients older than 75 years) with pharmacological use were analyzed.
The prevalence of pseudarthrosis in osteoporosis was found to be 59.34% (52.94 -65.54%), a fusion rate of 79.28% with teriparatide in the first six months, 95% CI OR 2.62 (1.79 -3.84).(Table 2) Regarding complications associated with osteoporosis, a screw loosening rate of 26.83% (21.5 -32.9%) was evidenced 12 months after surgery, with 18.1% screw loosening with the use of teriparatide,  13 29 To evaluate the effect of teriparatide on screw torque in fusion surgery patients with osteoporosis.
Administration of teriparatide one month before surgery improves screw torque at fusion.Cohort .R Kim (2018) 14 84 To determine the effect of teriparatide vs. bisphosphonates on screw loosening in spinal surgery in the osteoporotic patient.
Determine the efficacy of teriparatide in posterolateral fusion in osteoporosis.
There is an increasing trend in fusion with teriparatide 46% in the first six months concerning bisphosphonates 32%.No significant differences in multilevel lumbar fusion.
Prospective randomized multicenter clinical trial.
Ohtori (2012) 16 57 The fusion rate with teriparatide was 82% at eight months vs. 68% at ten months with bisphosphonates in posterolateral fusion.
Prospective R  10 16 Evaluating lumbar spinal fusion in osteoporosis with the addition of denosumab to teriparatide.
There is an increase in the rate of spinal fusion and bone formation with the combination of teriparatide and denosumab six months after surgery, p < 0.05.

Prospective randomized clinical trial R Ebina (2017) 20 78
To evaluate the fusion and increase in bone mineral density of teriparatide associated with denosumab and bisphosphonates.
Denosumab associated with teriparatide increases bone mineral density by 6.2 vs. 2.6% concerning bisphosphonates and teriparatide and decreases the rate of bone resorption.
Observational R Tseng (2012) 21 50 To evaluate the use of teriparatide alone vs. vertebroplasty plus bisphosphonates in managing vertebral fractures adjacent to previous vertebroplasty for osteoporosis.
Patients treated with teriparatide had a 78.5% decrease in vertebral fractures (post vertebroplasty) odds ratio=0.21;95% CI l, 0.02-2.10)with VAS (visual analog scale) decrease at six months P < 0.05, concerning the combination of new vertebroplasty and bisphosphonates.
Prospective randomized comparative R Kaliya-Perumal (2016) 22 62 To evaluate the effectiveness of teriparatide in multilevel lumbar fusion in patients with osteoporosis concerning placebo.evidencing a decrease in this complication of 81.9% with the use of this drug.OR 0.6 (0.41 -0.88).(Table 3) When comparing teriparatide with bisphosphonates, there was evidence of an increase in bone mineral density of 10.71% with a positive predictive value of 15.15% (5.72 -32.67%), indicating an increase of 4.5% more concerning bisphosphonates OR 1.49 (0.77 -2.86).(Table 4) Finally, there is a significant increase in vertebral fractures in patients older than 75 with osteoporosis, with a prevalence of 24.51% in patients who have undergone surgery or vertebroplasty, which was 14.55% with the use of teriparatide, indicating that the use of teriparatide decreased the risk of fractures in this population by 85.4%.OR 0.5 (0.29 -0.95).(Table 5)

DISCUSSION
The success or failure of spinal surgery in osteoporosis is determined by peri-operative planning, which consists of adequate diagnosis, prevention, and treatment.
Patients with osteoporosis in spinal surgery are prone to failure and poor postoperative results due to early and late complications, such as vertebral fractures, loosening of screws, pseudoarthrosis, and kyphosis of the proximal junction, among others. 24 wide spectrum of drugs has been used for the management of osteoporosis.However, teriparatide and bisphosphonates are the drugs with the most publications.Despite contributing to bone fusion in spinal surgery and reducing the risk of fractures, bisphosphonates have been associated with various complications, such as subtrochanteric fractures of the femur, diabetes mellitus, alterations in calcium homeostasis, and necrosis of the maxilla. 25,26ifferent uses of teriparatide have been described in spinal surgery, such as increased fusion, decreased screw loosening, increased bone mineral density, decreased incidence of vertebral fractures in patients older than 70 years, multilevel fusion, increased torque in pedicle screws, and a synergistic effect with the combination of denosumab in cases of severe osteoporosis.It is the duty of the spine surgeon as opposed to the endocrinologist to know its usefulness. 12egarding fusion, Cho 9 in 2017 performed a prospective cohort study with 47 osteoporotic patients in spinal surgery comparing teriparatide with bisphosphonates; they found a similar fusion rate in both groups at 12 and 24 months (92% vs. 96%); however, it was more accelerated with teriparatide in the first six months (77.8 % vs. 53.6%p 0.05), decreasing the presentation of complications described by bisphosphonates when used for a shorter time.Additionally, it found a greater increase in bone mineral density.Other studies 1,6,2,8,11,12,15,16,18,19,27 show that administration of teriparatide vs. bisphosphonates and placebo significantly increases spinal fusion OR 2.12,95% CI 1.45-3.11,p= 0.0001) and placebo (OR 2.23, 95% CI 1.22-4.08,p= 0.009) cohorts, respectively (1,6,9,18).Ebata 18 in 2018 similarly finds increased spinal fusion of 66% in teriparatide vs 35% placebo p0.0035.Current studies found a statistically significant 79% teriparatide fusion rate in the first six months, results that resemble the literature.IC 95% OR 2.62 (1.79 -3.84). 16,18,19,23he decrease in screw loosening has been similarly described in the literature using teriparatide and bisphosphonates.Kaliya -Perumal 22 finds 66.7% vs. 50% multilevel fusion using teriparatide vs. control without statistical significance P 0.2.However, 13.4% vs. 24.4% in screw loosening P 0.001.Kim 14, in 2018 performed a prospective study in 84 osteoporotic patients taken to elective spinal surgery and fusion, which administered teriparatide and bisphosphonates to the control group and found that loosening rates at six months were 6.9% and 6.8%, respectively, similar; however, the rate decreased markedly at 12 months in the teriparatide group 2.3% vs. 9.2% bisphosphonates without finding statistical significance P < 0.05.
In turn, Ohtori 17 in 2013 conducted a study in 62 patients with osteoporosis in elective spinal surgery to evaluate the incidence of screw loosening with the use of teriparatide 20 mcg per day for 12 months, bisphosphonates and placebo; he found loosening of 7 to 13% in teriparatide vs. 13 -26% in bisphosphonates and 15 -25% in patients who did not receive drugs P < 0.05.Additionally, in contrast to other studies performed in rats, in this study, it was possible to observe an improvement in bone quality with teriparatide and; an improvement of cancellous and cortical bone in the pedicle, which has repercussions on transpedicular fixation.In conclusion, teriparatide had a notable advantage concerning bisphosphonates in reducing screw loosening.Likewise, there were no differences between bisphosphonates and the group that received no drug.In our presentation, a screw loosening of 18.1% was observed using teriparatide without statistical significance.
Another important aspect of using teriparatide is related to increased bone mineral density and quality.Kim evidences a superiority of 14.86% vs. 8.5% in improving bone mineral density at 12 months of pharmacological treatment after surgery. 14An increase of 15.15% was observed using teriparatide at 12 months postoperatively with statistical significance OR 1.49 (0.77-2.86) and results similar to the literature. 19egarding the presentation of vertebral fractures, they are more frequent in patients over 75.Avoiding these fractures as they increase spinal deformity, worsen balance, produce lumbar pain or irradiation, and gastroesophageal reflux in most geriatric patients, thus worsening functional outcomes and quality of life and increasing the risk of mortality due to associated complications.Seki,19 in 2017 performed work on 58 patients with osteoporosis to compare the presence of postsurgical vertebral fractures when administering teriparatide vs. bisphosphonates.It finds that teriparatide better avoids complications and fracture incidence and maintains the fusion rate concerning bisphosphonates.Implant rupture or failure was higher in patients over 75 years of age P 0.002.For these reasons, he recommended an administration interval of 3 months before surgery to 12 months postoperatively.Tseng et al 24 found a greater decrease in the presentation of postoperative vertebral fractures with teriparatide compared to low-dose bisphosphonates associated with vertebroplasty.
In our study, we found a prevalence of osteoporotic vertebral fractures of 24.51%, teriparatide showed a decrease of 85.4% in the rate of postoperative vertebral fractures with a 14.55% superiority over bisphosphonates, without statistical significance; OR 0.5 (0.29 -0.95), similar to the results described in recent literature. 16,17iomechanically, teriparatide increases pedicle screw torque during spinal fusion surgery more efficiently concerning patients without pharmacological treatment (1.28 ± 0.42 Nm) vs control (1.08 ± 0.52). 24ther pharmacological lines have played an important role in the management of osteoporosis, such as Denosumab, and despite the existence of scientific evidence in the management of postmenopausal osteoporosis 13 and some pathologies such as giant cell tumor in the sacrum, multiple myeloma, and aneurysmal bone cyst; [28][29][30][31] there is still no evidence in the literature of clinical trials, comparative or prospective studies about its usefulness in elective spinal surgery of the osteoporotic patient. 2 Denosumab is the only monoclonal antibody approved by the FDA for the treatment of osteoporosis.Its pharmacological mechanism consists of preventing the binding of RANK to the RANKL receptor, 3 inhibiting early osteoclast differentiation. 5ifferent aspects of denosumab have been studied in spinal surgery.One of the main ones is the synergistic effect with teriparatide, with which an increase in resistance and improvement in bone microarchitecture has been observed.This implies superiority concerning monotherapy with teriparatide.Its effect has been observed with the administration of 60 mg subcutaneously every six months between 1 and 2 years. 28de 10 in 2018, conducted a study with 16 osteoporotic patients to evaluate spinal fusion with the use e teriparatide and teriparatide associated with denosumab one month before and 12 months after surgery, evidenced a greater fusion in the first six months with the pharmacological association concluding that it could be implemented in the treatment of severe spinal osteoporosis.Other authors have also investigated the synergistic effect of denosumab, even when compared to bisphosphonates, with promising results in spinal fusion (6.2 vs. 2.6 %; P < 0.01) in use for one year after surgery. 29n a 2-year prospective study, 21 patients with osteoporosis undergoing spinal surgery showed that Denosumab increases screw strength in the pedicle and vertebral body by increasing bone mineral density, being the first study to consider denosumab in spinal instrumentation. 3011][12]15,18 Although most of the time the endocrinologist manages it, the spine surgeon should know how to plan the surgery, reducing the number of complications and improving the patients' bone quality and life expectancy.There is still no consensus on the administration interval.However, most studies show that the greatest benefit of teriparatide is obtained when 20 mcg subcutaneous is administered daily before three months after surgery and up to 12 months later, since in this period, it not only increases fusion but also improves bone mineral density and reduces screw loosening. 6,7,14,22n reviewing the current literature, most studies show the advantages of teriparatide over bisphosphonates in terms of a faster rate of fusion in the first six months 8 , a lower rate of complications, increased torque, 21 improved bone quality 19,22,31 and a better effect in reducing the risk of vertebral fractures. 16,17We consider that denosumab should be associated with patients with severe osteoporosis due to its effects above. 9,31ore cost-effective clinical studies with a larger number of patients and a follow-up of more than two years are needed to evaluate new utilities and confirm the synergistic effect of denosumab.

Limitations of the study
1.There is a lack of controlled clinical trials to determine an adequate guideline and interval of teriparatide administration, as well as greater statistical power in the loosening of screws and reduction of vertebral fractures.2. There are no clinical studies on denosumab to determine its efficacy in osteoporosis of spinal surgery.3. Small patient samples 4. Heterogeneity of the population 5. Cost-effectiveness of teriparatide needs to be adequately evaluated.6. Clinical studies are required to evaluate the instrumentation results after 12 months.

CONCLUSIONS
The uses and advantages of teriparatide and denosumab in planning are different.They should be taken into account by the spinal surgeon and endocrinologist.Teriparatide was shown to increase fusion and bone mineral density while decreasing the rate of complications such as screw loosening and the incidence of vertebral fractures more effectively than bisphosphonates.
Denosumab has a synergistic effect with teriparatide in severe osteoporosis by increasing bone mineral density more effectively and, at the same time, decreasing screw loosening during instrumentation.However, clinical and comparative studies are lacking to verify its usefulness and greater statistical significance.
Due to their versatility, advantages over bisphosphonates, and low risk of complications, both drugs should be considered in the peri-operative planning of spinal surgery.Their use does not replace the different surgical methods and techniques that are also part of the planning.Each case should be evaluated individually, analyzing the risks and benefits.
All authors declare no potential conflict of interest related to this article.

Table 1 .
Selected articles meeting the inclusion criteria.

Table 2 .
Association of teriparatide and spinal fusion rate at six months.

Table 3 .
Association of teriparatide and screw loosening rate at 12 months.

Table 4 .
Association of teriparatide and increased bone mineral density compared to bisphosphonates.

Table 5 .
Association of teriparatide and decreased vertebral fractures compared to bisphosphonates in patients older than 75.All authors contributed substantially to the production of the article, jointly posing the question and planning.RCJ: analysis of the results with statistical evaluation and draft writing.PLB: Bibliographic search, initial selection of articles, and review of the draft.JCSA: Final selection of articles and translation of the article.