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1 Enhanced bone healing and decreased in sacral insufficiency fractures after teriparatide : retrospective clinical-based observational study Yuji Kasukawa 1,3 Naohisa Miyakoshi 1,3 Toshihito Ebina 2 Michio Hongo 1,3 Yoshinori Ishikawa 1,3 Daisuke Kudo 1,3 Koji Nozaka 1,3 Yoichi Shimada 1,3 1 Department of Orthopedic Surgery, Akita University Graduate School of Medicine, Akita, Japan 2 Department of Orthopedic Surgery, Kakunodate General Hospital, Senboku, Japan 3 Akita Bone and Osteoporosis Network (A-BONE) Address for correspondence: Yuji Kasukawa, M.D., Ph.D. Department of Orthopedic Surgery, Akita University Graduate School of Medicine Hondo, Akita , Japan Tel: ; Fax: kasukawa@doc.med.akita-u.ac.jp kasukawa@doc.med.akita-u.ac.jp Summary The purpose of this retrospective clinical-based observational study was to evaluate the effects of teriparatide (TPTD) on clinical outcomes and radiologic findings of sacral insufficiency fractures (SIFs). Seven elderly women with SIFs received TPTD for at least 6 months. We evaluated the symptoms,, and radiological findings. At their initial clinic visit, 86% patients could not walk or sit. Computed tomography (CT) images revealed sacral wing fracture in 6 patients, and bone scintigram showed H-shaped uptake over the bilateral sacral wings in 1 patient. After the, 5 patients could walk. Mean visual analog scale score was significantly lower after (12.9 mm) than before (87.4 mm) TPTD (p < ). CT images revealed bone union (four patients) and sclerotic changes (three patients) at the fracture sites. Seven elderly women with SIFs had significant improvement in and demonstrated bone union or sclerotic changes at fracture sites by TPTD. KEY WORDS: sacral insufficiency fracture; teriparatide; low back ; fracture healing; bone union; mobility. Introduction advanced osteoporosis. The incidence of SIFs has increased with the rapid increase in the size of the elderly population (1). Sacral fractures are a well-defined subgroup of pelvic insufficiency fractures. The mortality rate of pelvic insufficiency fracture patients, reported to be 16.3%, is comparable to that of hip fracture patients (2). Treatment of SIFs is very important for recovering patients ability to perform activities of daily living. However, the of SIFs is complicated by severely osteoporotic sacral bone, and the incidence of such fractures is increasing. There is no established best for SIFs. Conservative with bedrest and medication is common (3). However, patients cannot recover their mobility in the early stage, and risk of complications increases with longterm bedrest (4). Teriparatide (TPTD) (1-34 parathyroid hormone [PTH]), which has been prescribed to stimulate bone formation in cases of severe osteoporosis, may prevent these problems. Several studies have reported that TPTD enhanced bone healing or bone union after fracture or osteosynthesis surgery (5, 6); however, the effects of TPTD of SIFs on, fracture healing, and mobility are still unclear. Therefore, the purpose of this study was to evaluate the clinical and radiological findings of SIFs treated with TPTD in 7 elderly women with osteoporosis. Methods Original article Patients Beginning in April 2012, 7 women with osteoporosis (mean age, 76 years [range, years]) with SIFs were treated with TPTD at our institution, which is part of the Akita Bone and Osteoporosis Network (A-BONE). Written consent for inclusion in this study and its publication was obtained from all patients. This study was approved by the ethical committee of Akita University Graduate School of Medicine (No. 1509). Patients clinical backgrounds, including comorbidities, for osteoporosis, chief complaint at first visit, time to diagnosis, of TPTD administration, combined therapy, and follow-up periods were recorded (Table 1). TPTD Following the diagnosis of SIFs, subcutaneous injection of TPTD 20 μg daily (Forsteo, Eli Lilly and Company, Indianapolis, IN, USA) or 56.5 μg weekly (Teribone, Asahi Kasei Pharma Corp. Tokyo, Japan), was used depending on patients choice and convenience. Six patients (86%) received combined (non-steroid anti-inflammatory drugs were used for 4 patients; activated vitamin D was prescribed for 2 patients; and vitamin K, elcatonin, or tocilizumab for rheumatoid arthritis was treated for 1 patient, respectively). Sacral insufficiency fractures (SIFs) often occur, either spontaneously or after minor trauma, in the elderly persons with 140 Evaluations Patients mobility and visual analog scale (VAS) score Clinical Cases in Mineral and Bone Metabolism 2017; 14(2):

2 Teriparatide for sacral insufficiency fractures Table 1 - Patient backgrounds. were evaluated at their first visit to our institution and after 1, 3, and 6 months of TPTD. Computed tomography (CT) (Discovery CT750 HD; GE Healthcare, Wauwatosa, WI, USA) or bone scintigraphy (Symbia E Dual Head System, Siemens AG, Munich, Germany) was performed to evaluate the condition of the fracture site before TPTD. At least 3 months after initiating TPTD, CT was taken to check the status of fracture healing. Pre- and post- bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry at the forearm (Osteometer, DTX-200, Toyo Medic, Tokyo, Japan) or lumbar spine (QDR-4500 Delphi Bone Densitometer; Hologic, Inc., Bedford, MA, USA). Levels of cross-linked N-telopeptide of type I collagen (NTX; nmolbce/l) were measured in 4 patients and tartrate-resistant acid phosphatase-5b (TRACP-5b; mu/dl) was evaluated in 1 patient as a marker of bone resorption before and after. Pre- and post- serum concentrations of bone alkaline phosphatase (BAP; U/L) or intact N-telopeptide of type I pro-collagen (P1NP; μg/l) were measured as markers of bone formation in all patients. Statistical analyses Results are shown as mean ± standard deviation (). Paired t-tests were used to compare pre- and post- VAS, BMD, and bone-turnover markers. A probability of less than 0.05 was considered statistically significant. All statistical analyses were performed using Statistical Package for the Biosciences (SPBS), Version 9.54 (7). Results Age (years) Comorbidity Treatment for osteoporosis before fracture Chief complaint at first visit Time to diagnosis (days) Teriparatide dose Combined therapy Follow-up periods (months) Case 1 78 HT None Low back 23 Weekly NSAIDs 24 Case 2 76 RA Vit D, Vit K Low back 11 Daily Vit D, Vit 21 K, NSAIDs Case 3 83 HT None Buttock 30 Daily Elcatonin 21 Case 4 78 DM None Low back 21 Daily None 6 Case 5 78 MD Ris, Vit D Buttock 8 Daily NSAIDs 16 Case 6 66 RA,DM Vit D Right hip 3 Weekly Vit D, Bio 18 CRF (tocilizuma b) Case 7 76 HT SERM, Vit D, Left hip 20 Daily NSAIDs 16 Vit K Mean ± 76.4 ± ± ± 5.8 Notes: Vit. D = Activated Vitamin D, Vit. K = Vitamin K, NSAIDs = Non-steroidal Anti-Inflammatory Drugs, Bio = Biologics, HT = Hypertension, RA = Rheumatoid Arthritis, DM = Diabetes Mellitus, MD = Muscle Dystrophy, CRF = Chronic Renal Failure, Ris = Risedronate, SERM = Selective Estrogen Receptor Modulator, = Standard Deviation Mobility and VAS scores Table 2 presents results of mobility evaluation at the first visit and after 3 and 6 months of TPTD. Six of 7 patients had improvement in mobility and 1 showed no change from the initial level of mobility at 6 months with TPTD. As shown in Table 2, VAS scores after 1, 3, and 6 months with TPTD were all significantly lower than that of first visit (p < for all). MRI, CT and bone scintigraphy Magnetic resonance imaging (MRI) was performed in 4 patients. The fracture sites were seen as low-intensity changes on T1-weighted images and high-intensity changes on T2- weighted images (Table 3). CT revealed bilateral sacral wing fractures in 4 patients (Table 3 and Figure 1A) and right sacral wing fracture in 2 patients (Table 3 and Figure 1B). Only 1 patient showed no clear sacral fracture on CT. Bone scintigraphy was performed in 3 patients and revealed high uptake and H pattern at the sacrum (Figure 2). Based on these image findings, all patients were diagnosed with SIFs. CT revealed bony union of fractures in four patients between 6 and 12 months after initiating with TPTD (Table 3 and Figure 1C). Sclerotic changes at the fracture sites of the other patients were seen from 3 to 12 months after beginning with TPTD (Table 3 and Figure 1D). BMD and bone-turnover markers BMD was measured in 5 patients, at the forearm in 1 and at the lumbar spine in 4. Comparison of BMD pre- and post with TPTD is presented in Table 4. Bone-turnover markers were also measured in 5 patients (Table 5). Mean NTX value was higher after with TPTD than before, but it was not statistically significant. The boneformation markers BAP and P1NP were evaluated in 6 patients and in 1 patient, respectively. By 6-12 months after TPTD, mean BAP value had decreased, but not significant, in 4 patients. Clinical Cases in Mineral and Bone Metabolism 2017; 14(2):

3 Y. Kasukawa et al. Table 2 - Mobility and visual analog scale (VAS) score before and after. Teriparatide Mobility VAS score (mm) dose First visit 3 months 6 months First visit 1 month 3 months 6 months Case 1 Weekly Wheel chair Walk with Walk Case 2 Daily Stretcher Wheel chair Wheel chair Case 3 Daily Wheel chair Walk with Case 4 Daily Stretcher Walk with Case 5 Daily Stretcher Wheel chair Walk with support Discussion In the present case series, TPTD significantly and rapidly decreased low back, buttock, and hip caused by SIFs after 1 month of. Following the decrease in symptoms, patients mobility was also notably improved (e.g., from wheelchair or bedrest to walking with a ) after 3 months. CT revealed bony union at half of the fracture sites with 6 to 12 months of TPTD and sclerotic changes in the remainder of fracture sites with 3 to 12 months of. Conservative such as bedrest and medication Walk Walk Case 6 Weekly Wheel chair Wheel chair Wheel chair Case 7 Daily Walk with Walk with Walk Mean ± 87.4± ± 18.1* 24.6 ± 15.6* 12.9 ± 14.9* Notes: VAS = Visual Analog Scale, = Standard Deviation, *; p < VAS at first visit by paired t-test. Table 3 - MRI, CT, and bone scan before and after the. Teriparatid e dose MRI Fracture locations on CT Bone scintigram Post- fracture appearance on CT Time to CT evaluation of union/sclerotic change (months) Case 1 Weekly NA R, L sacral wings NA Union 10 R pubis Case 2 Daily T1 low, T2 high L pubis, T11, L1,2 H pattern Sclerosis 12 Case 3 Daily T1 low, T2 high R, L sacral wings R transverse process of L5 H pattern Union 9 Case 4 Daily T1 low, T2 high R, L sacral wings NA Sclerosis 3 Case 5 Daily NA R sacral wing R ischium Case 6 Weekly NA R, L sacral wings R pubis and ischium Case 7 Daily T1 low, T2 high R sacral wing L pubis H pattern Sclerosis 6 NA NA Sclerosis and union Sclerosis and union Notes: MRI = Magnetic Resonance Imaging, CT = Computed Tomography, R = Right, L = Left, NA = Not Applicable 3 and 6 8 and 12 has typically been used for SIFs (4, 8). However, because SIFs often occur in patients with severe osteoporosis, not only the, but also the osteoporosis, should be treated in these patients. Bisphosphonates are widely used for the of osteoporosis but can have an inhibitory action on bone turnover, and bisphosphonate immediately after fracture may delay healing by affecting normal bone metabolism and turnover at the fractures site (9). There is no report regarding the usefulness of bisphosphonates in healing SIFs. Several studies have reported surgical such as sacroplasty or percutaneous screw fixation for SIFs (10, 11), but the optimal surgical techniques and long-term 142 Clinical Cases in Mineral and Bone Metabolism 2017; 14(2):

4 Teriparatide for sacral insufficiency fractures Figure 1 - Computed tomography images of fracture sites. (A) Pre- bilateral sacral wing fractures (arrows). (B) Pre- right sacral wing fracture (arrow). (C) Bone union of bilateral fractures after 6 months of TPTD. (D) Right sacral wing fracture showing sclerotic change after 6 months of TPTD. Figure 2 - Posterior-anterior bone scintigraphy. Image reveals high uptake, with H shape at the sacral insufficiency fractures (black arrows). There was also high uptake at L1, T11, and right ribs, indicating osteoporotic fractures of the thoracolumbar lesion and ribs. Clinical Cases in Mineral and Bone Metabolism 2017; 14(2):

5 Y. Kasukawa et al. Table 4 - Bone mineral density before and after. Before After Time of BMD Teriparatide Site BMD BMD evaluation (months) dose (g/cm 2 ) (g/cm 2 ) Case 1 Weekly Forearm Case 2 Daily NA NA NA NA NA NA Case 3 Daily LS Case 4 Daily NA NA NA NA NA NA Case 5 Daily LS Case 6 Weekly LS Case 7 Daily LS Mean ± -3.9 ± ± ± 5.2 Notes: BMD = Bone Mineral Density, = Standard Deviation, NA = Not Applicable, LS = Lumbar Spine Table 5 - Bone turnover markers before and after. Teriparatide dose Bone resorption marker Bone formation marker Months after Type Before After Type Before After Case 1 Weekly NTX BAP Case 2 Daily NA NA NA BAP 29.2 NA NA Case 3 Daily NTX BAP Case 4 Daily NA NA NA BAP 44.6 NA NA Case 5 Daily NTX BAP Case 6 Weekly TRACP5b NA 531 P1NP Case 7 Daily NTX BAP Mean ± NTX (n = 4) 19.7 ± ± 8.4 BAP (n = 6) outcomes of these procedures are still unclear (12, 13). In the present case series, the major symptoms of SIFs, which were low back or buttock, rapidly decreased after 1 month of with TPTD. Several studies have demonstrated low back from vertebral fracture in patients with osteoporosis to be reduced with TPTD (14-18). A meta-analysis showed that TPTD significantly reduced the risk of moderate or severe back compared to placebo, alendronate, or hormone replacement therapy in the patients with osteoporosis (15). There are no data suggesting an analgesic effect of TPTD, and whether it possesses a mechanism of relief in SIFs remains unclear. It has been reported that intermittent administration of PTH stimulates fracture healing in animal models (19, 20). TPTD (20 μg daily) significantly reduced in time to cortical bone bridging of Colles fractures in postmenopausal women aged years (21). Peichi et al. reported that PTH 1-84 (100 μg daily) accelerated fracture healing of pelvic fractures, as evaluated by CT, and improved functional outcomes such 42.7 ± ± ± 2.4 Notes: NTX (nmolbce/l) = Cross-Linked N-Telopeptide of Type I Collagen, TRACP-5b (mu/dl)= Tartate-Resistant Acid Phosphatase-5b, BAP (U/L) = Bone Alkaline Phosphatase, P1NP (μg/l)= Intact N-Telopeptide of Type I Pro-Collagen, NA = Not Applicable, = Standard Deviation as, evaluated using a VAS, and mobility, assessed with a timed up-and-go test, in 65 patients with osteoporosis (22). Recent systematic reviews have indicated that TPTD plays an important role in fracture healing and promotes fracture healing in patients with osteoporosis (23, 24). In the present case series, TPTD did not show significant effects on BMD and bone turnover markers evaluated with NTX and BAP. However, TPTD does stimulate bone formation, even in SIFs, and can thus lead to healing and stabilization of the fracture site and a consequent reduction in. We identified only two case reports describing the of sacral insufficiency fractures with TPTD (25, 26). Both demonstrated that TPTD was effective in callus formation as well as of osteoporosis, and in the present case series, bony union or sclerotic changes were seen at the fracture sites after with TPTD. These previous studies and the present case series suggest that TPTD can be useful in the of SIFs in patients with severe osteoporosis. 144 Clinical Cases in Mineral and Bone Metabolism 2017; 14(2):

6 Teriparatide for sacral insufficiency fractures Conclusions In 7 elderly women with osteoporosis, daily or weekly TPTD of SIFs beginning within 30 days of onset significantly improved low back, buttock, or hip at 1, 3, and 6 months. CT revealed bone union or sclerotic changes at the fracture site in all patients after 6 months of TPTD. Consent Written informed consent was obtained from all patients for publication of this case report and any accompanying images. Competing interests The Authors declare that they have no competing interests. Acknowledgements The Authors thank the nursing staff of the Department of Orthopedic Surgery, Hospital of Akita University Graduate School of Medicine for their assistance to take care of the patients. No specific funding was obtained for this study. References 1. Harms JG, Jeszenszky D. The unilateral transforaminal approach for posterior lumbar interbody fusion. Oper Orthop Traumatol. 1998;10: Krappinger D, Kammerlander C, Hak DJ, Blauth M. 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