Effect of Systemic Teriparatide (PTH1-34) versus Placebo on Bone MineralDensity (BMD) after Lumbar Spinal Arthrodesis: A Secondary Analysis of aRandomized Clinical Trial

doi:10.21203/rs.3.rs-2234021/v1

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Effect of Systemic Teriparatide (PTH1-34) versus Placebo on Bone MineralDensity (BMD) after Lumbar Spinal Arthrodesis: A Secondary Analysis of aRandomized Clinical Trial

https://doi.org/10.21203/rs.3.rs-2234021/v1

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Background

The present study is a secondary analysis of data from a randomized, double-blind, placebo controlled clinical trial. Patients undergoing decompression and non-instrumented lumbar arthrodesis may have initial bone loss after surgery, increasing their fracture risk. The aim of this analysis is to determine whether short term systemic Teriparatide has a beneficial effect on Bone Mineral Density (BMD) in patients 60 years and older undergoing non-instrumented lumbar arthrodesis.

Method

Patients were 87 Danish patients eligible for spinal decompression and non-instrumented arthrodesis, who received either 20 micrograms Teriparatide (N=43) or placebo (N=44) daily for 3 months starting prior to surgery. Randomization and allocation were computer-generated. Outcome measures were BMD and Patient reported Outcome measures (PROs) containing Oswestry Disability Index (ODI) and Visual Analog Scale (VAS) for leg pain. DXA scans were performed preoperatively and at 1,3,6 and 12 months after surgery. PROs were collected at the same time points aside at 1 month after surgery. ANCOVA comparing Lumbar Spine BMD and Hip BMD in Teriparatide vs Placebo with gender, weight, age and baseline BMD as covariates were performed.

Results

There was some improvement in BMD in the Teriparatide group compared to placebo at 3 months after surgery, but not sustained at 6 and 12 months. There was a loss of Lumbar Spine BMD at 1 month after surgery in both groups.

Conclusion

Systemic Teriparatide provided a short term beneficial effect on BMD compared to placebo in patients undergoing decompression and non instrumented lumbar arthrodesis. There was an initial rapid bone loss 1 month after surgery in both groups.

The demographics of our society are changing with the global proportion of people over the age of 65 predicted to increase from 8,5% in 2015 to 16,7% in 2050, presenting new health challenges. One of these challenges is osteoporosis, with its attendant increased fracture risk leading to increased morbidity and mortality (1–3)

The North American National Institutes of Health (NIH) Consensus development Panel on Osteoporosis Prevention, Diagnosis and Therapy defines osteoporosis as “a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture. Bone strength primarily reflects the integration of bone density and bone quality” (4)

Multiple factors impact Bone Mineral Density (BMD). It is well documented that older age, female gender and previous fractures are associated with low BMD. (5) Weight loss and sedentary lifestyle have also been associated with low BMD. Nguyen (6) showed that both women with weight loss and women who were inactive had increased bone loss compared to women with stable weight and who were physically active. In 2008, Meyer (7) showed that weight loss also causes increased bone loss in men.

Loss in BMD after surgery may be expected, especially in patients after lumbar spine surgery with its associated perioperative decrease in physical activity and weight loss. Some studies investigated BMD in relation to Total Knee Arthroplasty (8, 9), but only few studies looked at BMD in relation to lumbar spine surgery(10, 11).

Parathyroid hormone (PTH) is a polypeptide consisting of 84 amino acids synthesized in the parathyroid gland, which is essential to regulation of bone remodeling with both anabolic and catabolic effects. The effect on bone mass depends on the dose and periodicity of the PTH signal. (12) This mechanism is utilized in the administration of the PTH-analogue Teriparatide (PTH 1–34) where a low dose is given intermittently to ensure an anabolic effect in osteoporotic patients.

We performed a randomized, double-blind placebo-controlled trial (13) to determine the effect of systemic administration of Teriparatide on fusion mass and quality compared to placebo. Study subjects were patients 60 years and older with lumbar spondylolisthesis undergoing decompression and non-instrumented lumbar arthrodesis. Dual X-ray Absorptiometry (DXA) scans were obtained in the subjects preoperatively and at 1,3,6 and 12 months after surgery. Data from this trial provides a unique opportunity to evaluate BMD in the Lumbar Spine and Hip in a temporal manner.

This study is a secondary analysis of data to investigate temporal changes in Hip and Spine BMD and its association with weight change and immobilization in patients aged 60 and older undergoing decompression and non-instrumented lumbar fusion and to determine whether systemic administration of Teriparatide had a beneficial effect on Hip and Spine BMD compared to placebo.

Trial design The present study is a secondary analysis of data from a prospective, randomized, double-blind placebo-controlled clinical study.

Participants Study subjects were 87 Danish patients, aged 60 years and older, undergoing spinal decompression and non-instrumented arthrodesis. Inclusion, operation and follow up were conducted from May 2011 to April 2017 at the Center for Spine Surgery and Research, Middelfart, Denmark. Inclusion criteria were patients with MRI and X-ray verified central spinal stenosis on 1–2 levels with spondylolisthesis and reduction in walking ability. Patients should have no sign of dementia, as evaluated by the Mini Mental State Examination (MMSE). Patients with fractures, comorbidity and previous spine surgery were excluded. Patients with limited walking ability caused by reasons other than spinal stenosis, such as parathyroid disease, cardiovascular or pulmonary disease, cancer, and orthopedic or rheumatologic disease of the lower limb, were also excluded.

Intervention Patients received either 20 micrograms Teriparatide subcutaneously (N = 43) or placebo (N = 44) daily for 3 months starting 1 day prior to the surgery.

Examinations DXA scans were performed preoperatively and at 1, 3, 6 and 12 months postoperatively. Weight was measured at the time of the DXA scans. Patient Reported Outcome Measures (PROs) including The Oswestry Disability Index (ODI) (14) and Visual Analogue Scale (VAS) (15) for leg pain were collected preoperatively and at 3, 6 and 12 months after surgery.

Outcomes The primary outcome in this study was the difference in BMD between the active treatment and placebo 1-year post-operative. In our secondary analysis we compared bone loss evaluated by DXA, weight change and self-reported functional level evaluated from ODI and VAS as a proxy for immobility. ODI is considered the gold standard for assessing disability due to back pain. The total ODI index as well as ODI question 4 concerning walking ability were included. VAS is a psychometric response scale, where the maximum score is 10 and minimum score is 0. The higher the score, the greater the patient’s complaint. In this study VAS concerning leg pain was included as a marker of immobility, assuming the greater the pain, the greater the immobility.

Randomization and blinding Participants were randomly allocated to receive Teriparatide or placebo treatment in 1:1 fashion by the ward nurse the evening before surgery, using a computer-generated randomization list. Randomization was performed in blocks of 10 at the hospital pharmacy. All participants, surgeons, investigators and staff were blinded to the treatment allocation. All files and data were saved on a secure online-based server at the hospital. The data is stored according to the Danish Open Administration Act, the Danish Act on Processing of Personal Data and the Health Act.

The trial was approved by the Scientific Ethics Committee of the Region of Southern Denmark (Eudra CT. # 2011-006152-36) and Danish Data Protection Agency. The trial is registered in ClinicalTrials.gov Feb 2013 (NCT2011-006152-36). For the present study a data processing agreement was obtained from the Region of Southern Denmark.

Statistical analysis First, descriptive statistics including mean with SD and CI of continuous variables were computed. Student’s t-test, both paired samples and independent were performed to compare continuous variables between subgroups and within each group over time. Multiple regression was conducted to evaluate risk factors for BMD decrease after surgery. ANCOVA comparing Lumbar Spine and Hip BMD in Teriparatide vs placebo with gender, weight, age and baseline BMD as covariates was performed. A p-value < 0,05 was considered statistically significant. Analyses were conducted with STATA 15 (StataCorp, 2000, College Station, TX: Stata Corporation, USA).

Surgical methods and primary results of the trial have been published elsewhere (13). Briefly the study found that 3 months Teriparatide after surgery did not increase fusion volume or improve the quality of the fusion mass in elderly patients compared to placebo after non-instrumented spinal fusion surgery for degenerative spondylolisthesis

Baseline characteristics of the study population are given in Table 1.

Table 1

Baseline characteristics
Variable	Teriparatide	Placebo	P-value
Patients, N	43	44	0.099
Female, N %	36,8	44,8	0.099
Age, years, Mean (SD)	71,1 (6,5)	70,4 (5,7)	0.592
Weight, kg, Mean (SD)	77.7 (11,8)	74.8 (11,9)	0.155
BMD Hip, g/cm², Mean (SD)	0.858 (0,1)	0.853 (0,1)	0.844
BMD Lumbar Spine, g/cm², Mean (SD)	0.942 (0,2)	0.952 (0,2)	0.766
ODI #4, Mean (SD)	2.2 (1,1)	2.4 (1,2)	0.488
ODI index, Mean (SD)	36.4 (12,2)	40.3 (12,6)	0.188
VAS leg pain, Mean (SD)	80.3 (145,8)	61.8 (143,2)	0.855

There was a significant bone loss in both groups at 12 months after surgery. For the placebo group the bone loss was 2.1% in Lumbar Spine and 1.6% in Total Hip.

There was a significant decrease in BMD for the Placebo group in Total Hip of 0.007 g/cm² between 6–12 months (p < 0.01) and for Teriparatide group BMD 0,007 g/cm² between 6–12 months (p < 0.01).The lowest BMD level for the Placebo group in Total Hip was 0.848 g/cm² at 12 months after surgery and for the Teriparatide group it was 0.856 g/cm² 12 months after surgery.

There was a significant decrease in BMD for the Placebo group in Lumbar Spine of 0.021 g/cm² between baseline and 1 month postoperatively (p < 0.001) and for the Teriparatide group it was 0.18 g/cm² (p < 0.01) between baseline and 1 month postoperatively. The lowest BMD level for the Placebo group in Lumbar Spine was 0.92 g/cm² 3 months after surgery and for the Teriparatide group it was 0.929 g/cm² 1 month after surgery.

Multiple regression analysis with age, gender, weight change, leg pain, ODI #4, and ODI index as independent variables, showed no significant associations. The Teriparatide group had significantly less BMD loss than the Placebo group at 3 months postoperatively with Teriparatide BMD at 0.876 g/cm² and placebo BMD at 0.845 g/cm² in the Hip (p < 0.001) and for the Spine Teriparatide BMD at 0.933 g/cm² and placebo BMD at 0.923 g/cm² (p < 0.104). These differences were not maintained at 6 and 12 months after surgery.

There was significant improvement of the ODI index in both groups between baseline and 3 months postoperatively (p < 0.001) and between 3 months and 6 months postoperatively (p < 0.01), with no significant difference between the groups between baseline and 3 months (p < 0.9) or 3 months and 6 months (p < 0.06). The same was applicable to ODI # 4, which was significantly improved in both groups between baseline and 3 months postoperatively (p < 0.001) and between 3 months and 6 months postoperatively (p < 0.01), with no significant difference between the groups between baseline and 3 months (p < 0.8) or 3 months and 6 months (p < 0.2).

When dividing participants into groups based on fusion rate (no fusion vs bilateral solid fusion), there was a significant decrease in Hip BMD in patients with no fusion between 6 months and 12 months at 0,008 g/cm² (p < 0.026). There was also a significant decrease in BMD Lumbar Spine between baseline and 3 months at 0,018 g/cm² (p < 0.001). There was a significant increase in Spine BMD in patients with solid fusion between 6 months and 12 months at 0,014 g/cm² (p < 0.03). There was no significant difference in Hip BMD in patients with solid fusion at any period. We have previously reported that there was no difference in proportions of fusion between the PTH group and the Placebo group. (13)

To the best of our knowledge this is the first study to evaluate the effect of systemic administration of Teriparatide on BMD after lumbar spinal surgery. We found a significant difference in Hip BMD between the Teriparatide group and the placebo group at 3 months, but this was not maintained at 6 and 12 months. Teriparatide treatment was administered only during the first 3 months and not followed up with anti-resorptive medicine, which could explain the lack of effect after 3 months.

At 12 months after surgery there was a significant bone loss in both the Teriparatide group and placebo group, however we could not determine if the bone loss in the study subjects differed from the expected annual age-related bone loss. Some earlier studies investigated bone loss in relation to spine surgery. Kawaguchi (10) hypothesized that due to the preoperative immobilization in this group of patients, the BMD would increase because of increased mobility after lumbar spinal surgery (decompression with or without fusion). The result from that study showed a BMD decrease in both Lumbar Spine and Femoral neck at 1 and 2 years after surgery, which they explained by decreased postoperative walking ability. Other studies which only evaluated local changes in Lumbar Spine BMD after spinal fusion surgery also found a postoperative decrease in BMD.(11, 16) The results from earlier studies supports our findings of a decrease in BMD after spinal fusion surgery, although none of the studies, including the present study, have evidence showing a significant deteriorated bone loss compared to the expected annual age-related bone loss.

A strength of our study is the high postoperative follow-up rate, which enabled us to see the initial rapid bone loss at 1-month after surgery. This initial bone loss indicates that patients undergoing decompression and non-instrumented lumbar arthrodesis have a period after surgery with a substantial increased fracture risk. Earlier studies suggest that a rapid bone loss can cause irreversible bone damage in terms of trabecular perforations which cause poor bone quality. (17, 18) Bone quality affects the choice of surgical techniques for reoperation, which makes the initial rapid bone loss a target for further research. (19)

We hypothesized insufficient nutrition and immobility as an explanation for postoperative bone loss. Insufficient nutrition measured by weight change were investigated, but there was no significant association between bone loss and weight change. The postoperative weight loss in our patients was however very modest.

In this study we found no effect of immobility as measured by ODI#4 and ODI index. ODI were chosen as the best possible measure of immobility, but still it is an indirect measure without validation. The study population consisted of patients with spinal stenosis, who had a reduced self-reported level of function, leg pain and hence immobility prior to surgery with a positive effect of the procedure regarding ODI and VAS.

We considered if the decrease in BMD was explained by calcium deposition in the bone graft. However, this was not the case, as both patients with solid bilateral fusion and with no fusion had a significant decrease in BMD. This makes the result more generalizable for patients not undergoing spinal fusion. However, this study was a secondary analysis and therefore had some limitations. One limitation was the very specific study population, who were immobile before surgery, which made it difficult to look at the association between BMD and immobilization due to surgery. To determine if the bone loss 12 months after surgery was greater than the expected annual age-related bone loss, a non-operated control group is needed. Besides the high follow-up rate, the strengths of this study were the RCT design and the homogenous group of patients, who all had spondylolisthesis treated with decompression and non-instrumented lumbar arthrodesis. Further studies are warranted to explore the impact of the initial rapid bone loss on bone quality.

Systemic Teriparatide provides a short term beneficial effect on BMD compared to placebo in patients undergoing decompression and non-instrumented lumbar arthrodesis. At 12 months postoperative there was a significant bone loss in both groups, however it was modest compared to the expected annual age-related bone loss.

Ethical Approval

All patients gave informed consent to participate and for data to get published before participating in this study.

The data is stored according to the Danish Open Administration Act, the Danish Act on Processing of Personal Data and the Health Act. The trial was approved by the Scientific Ethics Committee of the Region of Southern Denmark (Eudra CT. # 2011-006152-36) and Danish Data Protection Agency. Relevant approvals for the use of DaneSpine were obtained from Danish Data Protection Agency Region of Southern Denmark no. 16/1586.

The study was approved by review board of Center for Spine Surgery & Research, Spine Center of Southern Denmark, Lillebaelt Hospital, Østre Hougvej 55, DK-5500, Middelfart, Denmark. No approval number was needed.

The trial is registered in ClinicalTrials.gov Feb 2013 (NCT2011-006152-36). For the present study, a data processing agreement was obtained from the Region of Southern Denmark. The study was approved by the department's review board.

Competing interests

There are no competing interests for any of the authors.

Authors' contributions

Conception and design by MA, AJ, PH and LC. Acquisition and data by AJ. Analysis and interpretation of data by AG, MA, PH and LC. Drafting of the manuscript, statistical analysis and preparation of figures by AG with supervision by MA, PH and LC. All authors reviewed the manuscript.

Funding

The Center for Spine Surgery and Research, Spine Center of Southern Denmark, received funds in 2014 for the primary study on the effect of PTH versus placebo on fusion quality from Eli Lilly.

Availability of data and materials

The results presented in this article are based on sensitive personal information stored at Spine Surgery and Research Middelfart in compliance with EU and Danish legislation. This information will only be available outside the project team as fully anonymised data

Wan He DG, and Paul Kowal. An Aging World: 2015. Washington, DC: U.S. Government Publishing Office; 2016.
Sundhedsdatastyrelsen. Prævalens, incidens og behandling i sundhedsvæsenet for borgere med osteoporose2018 19.9.2919; 1:[6:110 p.].
Center JR, Nguyen TV, Schneider D, Sambrook PN, Eisman JA. Mortality after all major types of osteoporotic fracture in men and women: an observational study. Lancet. 1999;353(9156):878–82.
Osteoporosis prevention, diagnosis, and therapy. Jama. 2001;285(6):785–95.
Cummings SR, Melton LJ. Epidemiology and outcomes of osteoporotic fractures. Lancet. 2002;359(9319):1761–7.
Nguyen TV, Sambrook PN, Eisman JA. Bone loss, physical activity, and weight change in elderly women: the Dubbo Osteoporosis Epidemiology Study. J Bone Miner Res. 1998;13(9):1458–67.
Meyer HE, Sogaard AJ, Falch JA, Jorgensen L, Emaus N. Weight change over three decades and the risk of osteoporosis in men: the Norwegian Epidemiological Osteoporosis Studies (NOREPOS). Am J Epidemiol. 2008;168(4):454–60.
Beaupre LA, Rezansoff A, Clark M, Jen H, Lambert RG, Majumdar S. Bone Mineral Density Changes in the Hip and Spine of Men and Women 1-Year After Primary Cemented Total Knee Arthroplasty: Prospective Cohort Study. J Arthroplasty. 2015;30(12):2185–9.
Kim KK, Won YY, Heo YM, Lee DH, Yoon JY, Sung WS. Changes in bone mineral density of both proximal femurs after total knee arthroplasty. Clin Orthop Surg. 2014;6(1):43–8.
Kawaguchi Y, Nakano M, Yasuda T, Seki S, Hori T, Kimura T. Bone mineral density of the femoral neck is increased after successful lumbar spine surgery: a 2-year prospective analysis. Spine (Phila Pa 1976). 2013;38(6):E367-73.
Bogdanffy GM, Ohnmeiss DD, Guyer RD. Early changes in bone mineral density above a combined anteroposterior L4-S1 lumbar spinal fusion. A clinical investigation. Spine (Phila Pa 1976). 1995;20(15):1674–8.
Silva BC, Bilezikian JP. Parathyroid hormone: anabolic and catabolic actions on the skeleton. Curr Opin Pharmacol. 2015;22:41–50.
Jespersen AB, Andresen ADK, Jacobsen MK, Andersen MO, Carreon LY. Does Systemic Administration of Parathyroid Hormone After Noninstrumented Spinal Fusion Surgery Improve Fusion Rates and Fusion Mass in Elderly Patients Compared to Placebo in Patients With Degenerative Lumbar Spondylolisthesis? Spine (Phila Pa 1976). 2019;44(3):157–62.
Fairbank JC, Pynsent PB. The Oswestry Disability Index. Spine (Phila Pa 1976). 2000;25(22):2940–52; discussion 52.
Aitken RC. Measurement of feelings using visual analogue scales. Proc R Soc Med. 1969;62(10):989–93.
Myers MA, Casciani T, Whitbeck MG, Jr., Puzas JE. Vertebral body osteopenia associated with posterolateral spine fusion in humans. Spine (Phila Pa 1976). 1996;21(20):2368–71.
Boyd SK, Davison P, Muller R, Gasser JA. Monitoring individual morphological changes over time in ovariectomized rats by in vivo micro-computed tomography. Bone. 2006;39(4):854–62.
Campbell GM, Buie HR, Boyd SK. Signs of irreversible architectural changes occur early in the development of experimental osteoporosis as assessed by in vivo micro-CT. Osteoporos Int. 2008;19(10):1409–19.
Shea TM, Laun J, Gonzalez-Blohm SA, Doulgeris JJ, Lee WE, 3rd, Aghayev K, et al. Designs and techniques that improve the pullout strength of pedicle screws in osteoporotic vertebrae: current status. Biomed Res Int. 2014;2014:748393.

No competing interests reported.

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Effect of Systemic Teriparatide (PTH1-34) versus Placebo on Bone MineralDensity (BMD) after Lumbar Spinal Arthrodesis: A Secondary Analysis of aRandomized Clinical Trial

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