Parathyroid Hormone Injection Versus Vertebroplasty in the Treatment of Osteoporotic Vertebral Fracture in Old Age: A Retrospective Study of 58 Female Patients


 Background: While the indications of parathyroid hormone (PTH) in osteoporosis prevention and management have been established, its indications in the treatment of osteoporotic vertebral fractures remain unknown. This study aimed to compare the effects of intervention (percutaneous vertebroplasty followed by anti-resorptive agents) and conservative treatment (PTH administration) in patients with osteoporotic vertebral fractures, as well as to investigate the optimal duration of PTH administration. Methods: A retrospective study was conducted using data of patients treated for osteoporotic vertebral fractures between January 2015 and November 2019. Treatment was selected based on the patient’s age, comorbidities, and patient’s preference after explaining the expected advantages and disadvantages of each treatment. Group C was administered PTH injections once weekly, whereas Group I underwent vertebroplasty followed by the administration of anti-resorptive agents. Radiological and clinical parameters were analyzed between two groups.Results: This study enrolled 58 patients (77 vertebrae). Group C included 24 patients (38 vertebrae) with average age of 77.50 ± 7.19 years (range, 65–85 years), average bone mineral density (BMD) of −3.39 ± 0.86 (range, −2.5 to −5.8), average follow-up period of 27.47 ± 7.60 weeks (range, 12–49 weeks). Group I included 34 patients (39 vertebrae) with an average age of 76.20 ± 8.67 years (range, 65–92 years), average BMD of −3.35 ± 0.91 (range, −2.5 to −5.1), average follow-up period of 30.82 ± 10.95 weeks (range, 16–59 weeks). There was no significant difference between the two groups in initial demographic, clinical and radiographic parameters. Group I showed significantly better clinical and radiological outcome during the last follow-up. Regarding side effects in Group C, two cases of dizziness (8.3%), nausea and vomiting (8.3%) were reported. In Group I, cement leakage was found in 26 vertebrae (66.7%), and cement leakage complications were observed in four patients (11.8%). Conclusion: Conservative treatment using PTH injection demonstrated slower pain relief and lesser suppression of vertebral height loss than vertebroplasty. However, PTH injection demonstrated a lower risk of procedure-related complications. The patient’s age, preference, and general condition with respect to the procedure’s risk should be considered when determining treatment options for osteoporotic vertebral fracture in old age.


Introduction
Osteoporotic vertebral fracture is a typical fracture type caused by osteoporosis, with an incidence of 7.6-14% reported among women in their 60s and 30-45% among those in their 70s [1][2][3]. Osteoporotic vertebral fractures increase fracture risks in other vertebral bodies, and both repeated fractures and deformity progression at the fracture site can cause persistent pain and reduce the quality of life signi cantly [4][5][6]. Non-union or delayed union at the fracture site limits physical activities in the long term, and vertebral body collapse can lead to neurologic de cits; therefore, osteoporotic vertebral fractures may require operative treatment [7,8]. Early diagnosis and treatment of osteoporotic vertebral fractures are crucial for preventing pain and complications caused by non-union and pseudarthrosis [9].
The osteoporotic vertebral fractures treatment must not only achieve short-term goals, such as helping the patient return to his/her daily routine quickly and restoring his/her quality of life through pain control, but also achieve long-term goals, such as promoting bony union, minimizing vertebral body collapse, and preventing secondary fractures or bone density reduction [10]. An intermittent injection of parathyroid hormone (PTH) promotes the formation of the cortical bone and cancellous bone, and is thus commonly used to treat patients with severe osteoporosis who are at a high risk of osteoporotic fractures [11]. The suggestion of the use of PTH in the treatment of osteoporotic vertebral fractures is relatively recent.
Short-term follow-up studies have reported that PTH improves the bony union rate, reduces the time to union more signi cantly than anti-resorptive agents (i.e., bisphosphonates), and produces clinical results similar to those of percutaneous vertebroplasty (VP) [10,12,13]. Therefore, PTH may be clinically effective and useful in treating osteoporotic vertebral fractures. However, while the indications of PTH in osteoporosis prevention and management have been established, its indications in the treatment of osteoporotic vertebral fractures are not known. Thus, this study aimed to compare the effects of an existing treatment method (percutaneous VP followed by the administration of anti-resorptive agents) and PTH administration in patients with osteoporotic vertebral fractures. Furthermore, we aimed to investigate the optimal duration of PTH administration based on clinical and radiological parameters.

Materials And Methods
This study was approved by the Institutional Review Board of our hospital. Among all the female patients aged ≥65 years, who were admitted to the hospital for osteoporotic vertebral fractures from January 2015 to November 2019, 58 patients (77 vertebrae) with a follow-up period of at least 3 months were included. Plain radiograph and physical examination were performed for female patients who visited the emergency department or an orthopedic outpatient clinic for acute lower back pain complaint. Those with suspected osteoporotic vertebral fractures were admitted to the hospital for lumbar magnetic resonance imaging (MRI) and bone densitometry.
An acute vertebral fracture was con rmed based on low signals on T1-weighted images and high signals on T2-weighted images, respectively, on lumbar MRI. The mean bone mineral density (BMD) of the L1 to L4 vertebrae and that of femoral neck was measured. The mean BMD of the two vertebral bodies with the lowest bone density was used as the lumbar BMD. For the femur, the BMD excluding that of the Ward's triangle was used. Osteoporosis was de ned as a T-score ≤−2.5. Patients con rmed with osteoporotic vertebral fractures were subjected to either conservative treatment with weekly administration of 56.5 μg of teriparatide (Teribone ® , Asahi Kasei Pharma Corporation, Tokyo, Japan) or an intervention consisting of percutaneous VP followed by the oral administration of anti-resorptive agents (alendronic acid, Fosamax ® , Merck & Co., Inc. Kenilworth, NJ, USA). An appropriate treatment method was chosen for each patient after explaining each treatment's advantages and side effects and considering their preference, age, and general condition. In the conservative treatment group (Group C), PTH administration ceased only when their pain levels were clinically low and did not interfere with daily activities (visual analog scale [VAS] score ≤3). There were no signs of fracture progression on follow-up plain radiographs, and radiological parameters had stabilized. Anti-resorptive agents (denosumab, Prolia ® , Amgen Inc., Thousand Oaks, CA, USA) were then subcutaneously injected. The patients were examined for any side effects of PTH administration during hospital admission and outpatient follow-up. In the intervention treatment group (Group I), alendronic acid (Fosamax ® ), an oral anti-resorptive agent, was administered weekly following percutaneous VP. All procedures were performed by a single operator (YSP). The operator checked the patient's neurological status before performing the procedure, any cement leakage on plain radiographs, as well as any complications associated with cement leakage after the procedure. Patient's age, sex, and underlying diseases were investigated through a review of medical records, and clinical and radiological parameters were measured during hospital admission and outpatient follow-up. The exclusion criteria for patients were follow-up period <3 months, neurologic de cits at the time of their initial admission, tumor or infection at the fracture site, proof of secondary osteoporosis based on their records of underlying diseases or medication prescriptions, and history of osteoporosis treatment before receiving treatment at the present hospital.
Following hospital discharge, all patients visited the outpatient clinic 1 month after treatment. They visited the clinic monthly until 3 months after the start of the treatment, after which they visited the clinic every 3 months. Pain levels were measured using the VAS at the time of admission and during the outpatient follow-up. MRI was used at the time of admission to identify the type of acute vertebral fracture (compression fracture or stable burst fracture) and the fracture site (thoracolumbar: T9-L2, or lumbar: L3-L5). The local kyphotic angle at the fracture site and the compression rate and its changes were measured on plain radiographs during admission and outpatient follow-up. The local kyphotic angle was de ned as the angle between the upper and lower endplates of the fractured vertebra. The compression rate was calculated using Mumford's method, which calculates the anterior height of the fractured vertebra by taking the mean of the anterior heights of the upper and lower vertebrae of the fractured vertebra [14].
Two examiners (ICK and BJK) independently measured radiological parameters. The measurement was repeated after 1 month to assess the intraobserver reliability.
When comparing the demographic, radiological, and clinical characteristics of the patients of the two groups, an independent t-test was used for continuous variables, and a chi-square test or Fisher's exact test was used for categorical variables. A paired t-test or Wilcoxon signed-rank test was used to examine the changes in each group's follow-up period. Intraclass correlation coe cients were used to measure the degree of agreement between the measurements of continuous radiological variables. All statistical analyses were performed using Statistical Package for the Social Sciences version 20.0 (SPSS Inc., Chicago, IL, USA). The level of statistical signi cance was set at p <0.05.

Results
In this study, 58 patients were analyzed. Group C included 24 patients and 38 vertebrae, and Group I included 34 patients and 39 vertebrae. No signi cant differences in age, fracture type, fracture level, mean number of fractured vertebral bodies, BMD and initial VAS scores were found between the two groups (Table 1). While there was no difference in the mean follow-up period between the two groups, Group I showed a signi cantly shorter time to achieve a level of pain that did not interfere with daily activities (VAS ≤3) as compared to Group C (1.54 ± 0.74 weeks vs. 9.25 ± 5.08 weeks; p < 0.05). In Group C, there were signi cant differences between the initial and nal measurements of the local kyphotic angle (10.38 ± 7.74° vs. 13.78 ± 9.40°; p < 0.05), height of fractured vertebra (  The measurements for the local kyphotic angle had an excellent interobserver reliability of 0.846. The height of the fractured vertebra and compression rate also showed excellent interobserver reliability. Moreover, the intraobserver reliability for the measurements obtained after 1 month by two examiners was rated as "excellent" to "very good" (Table 3). In one case, the cemented foreign body was removed under general anesthesia because of acute chest pain and heart failure induced by the leaked cement that entered the heart through the bloodstream following percutaneous VP. In another case, the leaked cement caused pulmonary thromboembolism, and two cases showed neurologic de cits (Table 4). Both cases of neurologic de cits showed transient motor weakness and paresthesia in the dermatome that disappeared within a few weeks of follow-up (Fig 3).

Discussion
PTH is a bone forming agent that signi cantly reduces the risk of osteoporotic vertebral fracture and treats it effectively, especially in multiple level fractures [6,15,16]. While previous studies reported that conversion to anti-resorptive agents is necessary after 2 years of PTH administration for the treatment of osteoporosis, there is no standard duration of PTH administration established for acute osteoporotic vertebral fractures [17][18][19]. This study compared the conservative treatment group (Group C) and the intervention treatment group (Group I). Group C was administered PTH weekly until VAS scores reached ≤3 and radiological parameters had stabilized, followed by administration of anti-resorptive agents, whereas Group I was administered oral anti-resorptive agents after percutaneous VP. Group C required an average of 9.25 ± 5.08 weeks (range, 4-22 weeks) to achieve VAS scores ≤3 and 16.44 ± 7.37 to 24.65 ± 8.75 weeks for the stabilization of radiological parameters.
Although percutaneous VP is commonly used to treat osteoporotic vertebral fractures, studies have reported that patients still experience di culty in returning to a daily routine after this procedure [20,21]. Although percutaneous VP is effective in relieving acute pain, it has certain limitations. Percutaneous VP showed no signi cant difference in symptom relief when compared to conservative treatment at 12 months after the onset of a fracture and no evident symptom relief when compared to a sham procedure [22][23][24][25]. There have been reports of interruption of bony union at the fracture site by the injected bone cement and occurrence of re-fracture at the site of cement injection [26]. The leakage of the cement injected into a fractured vertebra can cause unexpectedly severe complications [27]. In a study that compared the ndings from a 3-month follow-up of patients undergoing PTH treatment or percutaneous VP, the latter signi cantly relieved pain in the rst week and increased the height of the fractured vertebra at 3 months after the onset of the fracture. However, it did not show a signi cant difference in the pain level and the ability to perform daily activities after 3 months when compared to PTH treatment. Moreover, there were lower medical expenditures reported in the PTH group as compared to the percutaneous VP group [10].
Previous studies on PTH examined patients with osteoporotic vertebral fractures without dividing them according to the severity of osteoporosis, and these studies only included patients with fractures of a single vertebral body. In such cases, a sample population may predominantly consist of patients with mild to moderate osteoporotic vertebral fractures. Hence, it may appear as if the patients responded well to conservative palliative treatments, such as simple bed rest, thus limiting an accurate assessment of the effects of different treatments. In the present study, a treatment plan was selected after considering patients' general conditions, BMD and number of fractured vertebral bodies. The current retrospective study setting included treatment groups resembling real-world patients more closely. Group C had a higher mean number of fractured vertebral bodies as compared to Group I (1.58 vs. 1.15), although the difference was not statistically signi cant. Including severe patients with the lowest BMD (T-score: −5.8) in Group C also emphasized the close setting to the real world.
It took an average of 9.25 weeks for the pain to reduce to a level that did not interfere with daily activities. However, it took 4-6 months (16.44-24.65 weeks) until the radiological parameters stabilized. A study that used plain radiographs and computed tomography to assess the continuity of cancellous bone showed that bony union took an average of 2.8 months to reach bony union through the weekly administration of PTH [13]. In our study, the local kyphotic angle, height of fractured vertebra, and compression rate were used instead of cancellous bone continuity to assess bony union, and the time to achieve bony union differed from that reported in previous studies. The results of this study suggest that it is advisable to continue the use of PTH in patients with osteoporotic vertebral fractures even after their VAS scores improve. Based on previous reports, it may be necessary to maintain PTH administration for 3-6 months after the initial administration. While percutaneous VP is an effective treatment option for acute osteoporotic vertebral fractures, its use is limited in patients with multiple vertebral fractures or underlying diseases, elderly patients, and cases where patients or their legal guardians do not consent to the operation. Percutaneous VP poses a severe risk of cement embolisms in patients with cardiovascular diseases.
Therefore, cement leakage and the resulting complications have been considered severe problems with percutaneous VP. Cement leakage may be asymptomatic, or it may cause complications such as pulmonary thromboembolism, nerve root and cord compression, and neurologic de cits [27,28]. These complications were observed in this study as well. In most cases of cement leakage, patients experience no symptoms or only mild and transient symptoms. However, as observed in previous studies and this study, cement leakage can also cause lethal complications such as pulmonary thromboembolism and cement migration to the heart. These complications would most likely require additional procedures or operations, which not only places a physical burden on elderly patients, but also increases the duration of hospital stay and medical expenses. Although several protocols have been proposed to prevent cement leakage, extra caution is required when injecting cement in patients with severe osteoporotic vertebral fractures, as they are at a signi cant risk of cement leakage [29][30][31]. A previous study reported that the group receiving PTH for 3 months had signi cantly lower medical expenditures than the group undergoing percutaneous VP. This suggested that PTH is a good treatment option in elderly patients with severe osteoporotic vertebral fractures [10]. In this study, two cases of dizziness and two of nausea or vomiting were reported in the group that was administered PTH. However, these symptoms were not severe enough to cease treatment and were relieved through conservative treatment. The two most commonly reported side effects of PTH are dizziness and lower leg cramps. Other common side effects include nausea, arthralgia, fatigue, headache, and hypertension [32,33]. A previous study reported that these side effects usually start in the early treatment period and rarely occur after 3 months of treatment [17]. This report is consistent with the results of the present study in which side effects occurred in the early treatment period and were relieved with conservative treatment. Hence, it is necessary to inform patients before starting the treatment that the aforementioned symptoms, albeit mild, may occur in the early treatment period in order to form a therapeutic relationship and ensure high compliance of the patients.
The limitations of this study include the single-center retrospective design, small sample size and relatively short follow-up period. A prospective randomized controlled trial for patients with severe osteoporotic vertebral fractures is warranted to understand the differences between PTH and conventional procedures, and to establish a more precise standard for PTH administration.

Conclusions
Conservative treatment using PTH in osteoporotic vertebral fractures achieves pain relief more slowly and prevents fracture site compression to a limited extent as compared to intervention procedures. However, it achieves evident symptom relief and does not cause side effects usually resulting from anesthesia and surgical procedures. Therefore, conservative treatment using PTH may be performed as a new and effective treatment method in patients with severe osteoporotic vertebral fractures who are of advanced age or show poor general conditions. When choosing an appropriate treatment method for osteoporotic vertebral fractures, it may be advisable to consider the patient's age, general conditions, and preferences regarding the treatment and the risks of surgery. Five months after PTH injection, plain radiograph shows height loss at T9, L1, L4, and L5 levels of 11.28%, 21.68%, 26.24%, and 19.07%, respectively (C). Five months after PTH injection, plain radiograph shows height loss at T9, L1, L4, and L5 levels of 11.28%, 21.68%, 26.24%, and 19.07%, respectively (C).   Case of a 79-year-old woman visiting the emergency room for lower back pain caused by slippage from ground level. Patient had undergone vertebroplasty of T12 and posterior fusion and pedicle screw xation from L3 to S1 15 years ago because of L4 burst fracture and T12 compression fracture in a car accident.
She was diagnosed as osteopenia (T-score: -1.4) at that time. Initial radiograph and T2-weighted magnetic resonance imaging show acute compression fracture at L2 (arrow) (A, B). Postoperative plain radiograph shows cement injected at the L2 vertebral body (arrow) (C). Postoperative computed tomography shows leaked cement right side of spinal canal at L1-L2 level (D, E). Patient showed transient motor weakness of right hip exor muscle with hypoesthesia on anterior aspect of right thigh. Her motor weakness improved within a week and was discharged as an independent ambulation status. Figure 3