Journal of Orthopaedic Science xxx (2017) 1e6

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Journal of Orthopaedic Science

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Original Article Effectiveness of monotherapy and combined therapy with calcitonin and minodronic acid hydrate, a bisphosphonate, for early treatment in patients with new vertebral fractures: An open-label, randomized, parallel-group study

* Shinya Tanaka a, , Akira Yoshida b, Shinjiro Kono a, Manabu Ito c a Department of Orthopaedic Surgery, Saitama Medical University, 38 Morohongo, Moroyama-cho, Iruma-gun, Saitama, 350-0495, Japan b Yoshida Orthopedics Clinic, 49-54 Tateishi, Matsumae-City, Hokkaido, 049-1501, Japan c National Hospital Organization Hokkaido Medical Center, Yamanote 5-7, Nishi-ku, Sapporo, Hokkaido, 063-0005, Japan article info abstract

Article history: Background: Evidence related to the effectiveness of combination drug therapy for the treatment of Received 5 February 2016 osteoporosis is currently considered insufficient. Therefore, this study was performed to clarify the ef- Received in revised form fects of monotherapy, and combination therapy, with a bisphosphonate (minodronic acid hydrate), a 14 December 2016 bone resorption inhibitor, and calcitonin (elcatonin), which is effective for the alleviation of pain due to Accepted 20 December 2016 vertebral fractures in osteoporotic patients. Available online xxx Methods: Study participants comprised of 51 female subjects with post-menopausal osteoporosis, whose main complaint was acute lower back pain caused by vertebral fractures. Subjects were randomly allocated into three groups and then administered with either intramuscular injections of elcatonin at a dose of 20 units weekly, minodronic acid hydrate at a dose of 1 mg daily, or a combination of these two drugs. As primary endpoints, time-dependent changes in levels of pain were assessed using a visual analog scale from baseline to 6 months of duration. In addition, we examined the effects of mono- therapies, and a combination therapy on bone resorption, with changes in bone mineral density at 4 sites and advanced hip assessment parameters from baseline to 6 months. A two-tailed significance level of 5% was used for hypothesis testing. Results: Elcatonin monotherapy showed some alleviation of pain immediately after any vertebral frac- tures, which was more than in the minodronic acid hydrate monotherapy group. In addition, the min- odronic acid hydrate monotherapy group experienced more effective inhibited bone resorption than the elcatonin monotherapy group. In the combination therapy, the efficacy for alleviating pain and inhibiting bone resorption was equivalent to the effect observed in the elcatonin and minodronic acid hydrate monotherapy groups respectively, with further improved values of bone mineral density observed in the femoral neck and lumbar vertebrae, and in parameters of advanced hip assessment compared with both monotherapy groups. Conclusions: Combination therapy with elcatonin and minodronic acid hydrate appears to be an effective treatment for osteoporosis patients with lower back pain, caused by fresh vertebral fractures. © 2016 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.

1. Introduction are included in guidelines for the prevention and treatment of osteoporosis [1]; however, these recommendations are based A number of new osteoporosis drugs have been introduced to solely on evidence from clinical trials in which the effects were the market in recent years, thus patients with osteoporosis have determined in a standardized and controlled patient population. an increasing number of available drug choices and administra- In actual clinical practice, various patient characteristics are taken tion methods. Recommendation grades for each of these drugs into consideration when selecting treatment options such as combination therapy. Although the effectiveness of combination * Corresponding author. Fax: þ81 49 276 1772. therapy for the treatment of osteoporosis has recently been E-mail addresses: [email protected] (S. Tanaka), [email protected]. investigated in numerous multicenter studies, led by groups such jp (S. Kono). http://dx.doi.org/10.1016/j.jos.2016.12.021 0949-2658/© 2016 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.

Please cite this article in press as: Tanaka S, et al., Effectiveness of monotherapy and combined therapy with calcitonin and minodronic acid hydrate, a bisphosphonate, for early treatment in patients with new vertebral fractures: An open-label, randomized, parallel-group study, Journal of Orthopaedic Science (2017), http://dx.doi.org/10.1016/j.jos.2016.12.021 2 S. Tanaka et al. / Journal of Orthopaedic Science xxx (2017) 1e6 as the Adequate Treatment of Osteoporosis Research Group [2], medical visits at 1, 2, 3 and 4 weeks, and 2, 3, and 6 months. In order sufficient evidence is still lacking. Therefore, in this present study, to examine the effects on bone metabolism, tartrate-resistant acid we investigated the effects of combination therapy with mino- phosphatase 5b (TRACP-5b), a marker of bone resorption was taken dronic acid hydrate (MIN), a bisphosphonate developed in Japan at baseline and at 2 and 4 weeks, also at 3 and 6 months after the for osteoporosis, and elcatonin (EL), an analog of eel calcitonin, a start of the study. Blood samples were collected before medical bone resorption inhibitor, for pain, bone resorption, bone mineral visits at each observation time point. density (BMD), and bone structure in patients who visited our In addition, at baseline and 6 months, the BMD of the lumbar outpatient clinic with acute lower back pain caused by new vertebrae (mean of L2eL4) and left proximal femur (total hip and vertebral fractures. femoral neck) was measured using dual-energy X-ray absorpti- ometry (DEXA) (Prodigy Advance, GE Healthcare, Madison, WI). 2. Materials and methods However, if there was a vertebral fracture in L2eL4, they were excluded from the calculation of the lumbar vertebral BMD value. 2.1. Study design 2.4. Efficacy endpoints This was an open-label, randomized, parallel-group study con- ducted between August 8, 2010 and March 31, 2011, that compared Primary endpoints of the study were time-dependent changes 3 treatment groups, EL group, MIN group, and EL þ MIN group. in VAS pain scores. The trends in changes from baseline were Patients were allocated into 3 groups using a sealed envelope compared between each of the three treatment groups. method, and received either intramuscular injections (IM) of EL The secondary endpoints were inhibition of bone resorption ® (Elcitonin , Asahi Kasei Pharma Co., Ltd., Tokyo, Japan) at a dose of based on changes in TRACP-5b levels; percent changes in BMD of 20 units weekly (EL group), an oral administration of MIN (Ono the L2eL4 vertebrae, total hip and femoral neck; and percent Pharmaceutical Co., Ltd., Osaka, Japan) at a dose of 1 mg daily (MIN change in advanced hip assessment (AHA) parameters. The AHA group), or a combination of these two drugs (EL þ MIN group). Each based on three variables, cortical bone instability (buckling ratio group received treatment for 6 months. [BR]), torsional resistance (section modulus [SM]), and cross- This study was conducted at the Yoshida orthopaedic clinic in sectional moment of inertia [CSMI] at the femoral neck were accordance with the ethical principles of the Declaration of Hel- calculated by the software incorporated into DXA system. CSMI is sinki, and was approved by the Hokkaido university's ethics derived from the integral of the bone mass profile across the bone committee. weighted by the square of distance from the center of mass. BR is calculated as the ratio of maximum distance from the center of 2.2. Subjects mass to the outer cortical margin divided by the mean cortical thickness. SM is calculated as CSMI divided by the greater of the The selection criteria for this study was as follows: post- measured distances from the center of mass to the medial or lateral menopausal women; 50 years of age at the start of treatment; surface [4]. developed acute lower back pain (defined as the area between the inferior pole of the scapula and the gluteal sulcus), which was 2.5. Discontinuation criteria and adverse events (AEs) identified within the previous 2 weeks and caused by new osteo- porotic thoracolumbar vertebral fractures [3]. Patients with either The discontinuation of the study was deemed necessary due to lower back or percussion pain were considered eligible for inclu- the following: if a subject withdrew their consent or no longer sion if they had new vertebral fractures confirmed by both X-ray wished to participate in the study; if it was discovered after the and magnetic resonance imaging (MRI). Regarding MRI examina- start of the study that the subject did not meet the inclusion tions, areas with low signal intensity on T1-weighted images and criteria; if the subject could not continue the study due to com- high signal intensity on T2-weighted images were considered plications or disease progression; or if there were any other non- incident fracture sites. specific reasons that warranted discontinuation. Before the study began, the study's aims and content were Any AEs reported through medical inquiries, or volunteered by explained by the attending physician, and written informed con- the subjects, were to be confirmed. sent was obtained from all patients. Patients with any of the following were excluded from the study: secondary osteoporosis; a 2.6. Statistical analysis history of thoracolumbar vertebral surgery; signs of neurological deficit associated with spinal disorders; severe scoliosis; contra- In order to ensure reliability, all data was sent to SOC Co., Ltd. indications for either of the treatment drugs (EL, MIN); infectious (Tokyo, Japan) from the clinic for statistical analysis. The results spinal diseases; severe kidney, liver, or heart disease; or currently were sent to the corresponding author. undergoing treatment for malignant tumors. To investigate the effects of the drugs, we analyzed VAS scores The use of any other osteoporosis drugs during the study was and TRACP-5b levels using repeated measured analysis of variance prohibited. In addition, from the time the study began until the (ANOVA), including an analysis of the interaction among the three administration of the treatment drugs ended, the use of oral or groups (EL group, MIN group, EL þ MIN group) with observation injected nonsteroidal anti-inflammatory drugs (NSAIDs) and non- time points set as explanatory variables. When a marked interac- NSAID analgesics was prohibited. However, if suppository NSAIDs tion was observed, the time-dependent changes were assumed to were required, duration of use, method and dose were all recorded. be different between the groups, and thus compared at each The use of treatments such as thermal or silver spike point therapy, observation time point. ANOVA was used to assess the effects on removable braces, or topical NSAIDs were all permitted. BMD (percent change) and AHA (percent change) between the groups. For multiple comparisons, p values were adjusted in 2.3. Assessments accordance with the Bonferroni method. A two-tailed significance level of 5% was used for hypothesis testing. SAS ver. 9.3 (SAS Pain was assessed using a visual analog scale (VAS) before the institute Japan Ltd., Tokyo, Japan) was used for all statistical start of the study (baseline), and prior to EL administration during analyses.

Please cite this article in press as: Tanaka S, et al., Effectiveness of monotherapy and combined therapy with calcitonin and minodronic acid hydrate, a bisphosphonate, for early treatment in patients with new vertebral fractures: An open-label, randomized, parallel-group study, Journal of Orthopaedic Science (2017), http://dx.doi.org/10.1016/j.jos.2016.12.021 S. Tanaka et al. / Journal of Orthopaedic Science xxx (2017) 1e6 3

3. Results groups. No significant differences were found between the EL and MIN groups (Fig. 2). The subjects' characteristics are shown in Table 1. All patients completed the study, and no AEs were reported. 4. Discussion

3.1. Pain assessment (VAS scores) Vertebral fractures are the most common type of osteoporotic fracture, and are known to significantly decrease a patient's Improvements in pain scores were evident in all groups at all ability to perform activities in daily life (ADL), it also lowers observation time points compared with baseline (Table 2). A quality of life (QOL) [5,6]. Furthermore, vertebral fractures have marked interaction was observed (p < 0.001) by ANOVA. At base- also been shown to negatively affect a patient's survival and line, the MIN group had a insignificant lower VAS score than the prognosis [7]. As a countermeasure, exercise therapy, nutritional EL þ MIN group and a significantly lower score than that of the EL therapy, and administration of osteoporosis drugs are undoubt- group. However, a reverse trend was observed at subsequent time edly important. Additionally, improving the treatment continua- points, as the EL þ MIN group showed significantly lower scores tion rate and administering powerful treatments to prevent than the MIN group at 1 week and 2 weeks, and both the EL þ MIN fractures are necessary in high risk patients. In particular, having and EL groups demonstrated significantly lower scores than the an existing vertebral fracture increases the risk of fractures at MIN group from 3 weeks to 3 months. No significant differences new sites [8]. Indeed, if a fracture spans over multiple vertebral were observed at 6 months. bodies, the risk of future fractures is three times greater than that of a patient with a fracture at a single vertebral body [9].To 3.2. Bone resorption inhibition (TRACP-5b) prevent such a chain of events, osteoporosis treatment should be introduced quickly after a fracture occurs. In patients who suffer Compared to baseline, TRACP-5b levels decreased in all groups, an osteoporotic vertebral fracture, it is important to start drug suggesting that bone resorption had been inhibited (Table 2). A therapy not only to reduce the risk of a secondary fracture, marked interaction was observed (p < 0.001). At baseline, the EL but also to prevent fracture-induced pain and declines in ADL group tended to have lower TRACP-5b levels than the other two and QOL. groups, but this difference was not significant. The MIN group had In this study, we compared the therapeutic usefulness of EL and significantly lower TRACP-5b levels than the EL group at 2 weeks, 3 MIN monotherapies and combination therapy in patients with new months, and 6 months, and the EL þ MIN group had significantly vertebral fractures who visited our outpatient clinic with the main lower levels than the EL group at 2 weeks and after. complaint of acute lower back pain. Comparisons between mono- therapy groups showed that the EL group tended to have improved 3.3. Bone mineral density (BMD) pain scores quicker than the MIN group. In contrast, the MIN group showed greater changes in TRACP-5b levels and a tendency of an Baseline BMDs of the L2eL4 vertebrae, at total hip and femoral increased value in total hip and femoral neck BMD. Combination neck, were greater in the EL group compared with the other two therapy exhibited effects for pain and TRACP-5b levels similar to groups, however, none of these differences were significant those using only EL and MIN, respectively. However, compared to (Table 1). monotherapy, combination therapy led to greater improvement in Comparisons between groups showed a significantly greater BMD at the L2eL4 vertebrae and femoral neck, as well as the AHA- BMD-increasing effect in the EL þ MINs group than in the other two related SM and CSMI. groups at the L2eL4 vertebrae and femoral neck, and in the In an ovariectomized rat study, Ogawa et al. reported that EL in EL þ MIN group, compared to the EL group in the total hip (Fig. 1). combination with alendronate improved BMD, bone structure, and There were no significant differences in the change in BMD be- bone strength more than with independent use of each drug [10]. tween the EL and MIN groups. However, in two previous studies reported by Hongo et al. and Takakuwa et al., additive effects of combination therapy with 3.4. Advanced hip assessment (AHA) risedronate and EL on BMD were not shown [11,12]. Our study, combined MIN and EL, and first demonstrated that combination Comparisons between the groups showed significantly greater therapy increased BMD as well as improved bone structure SM and CSMI changes in the EL þ MIN group than in the EL and MIN compared with the administration of each drug individually.

Table 1 Patient backgrounds at baseline.

Number of patients (n) EL group MIN group EL þ MIN group Between-group comparison (Bonferroni correction) Sex (male/female) 16 17 18 EL vs EL vs MIN vs 0/16 0/17 0/18

Mean ± SD Mean ± SD Mean ± SD MIN EL þ MIN EL þ MIN

Age (yrs) 75.5 ± 6.8 72.6 ± 7.0 78.1 ± 6.7 p ¼ 0.704 p ¼ 0.809 p ¼ 0.065 Height (cm) 149.3 ± 3.8 149.2 ± 4.9 146.1 ± 5.6 p ¼ 1.000 p ¼ 0.180 p ¼ 0.201 Weight (kg) 46.6 ± 5.8 48.1 ± 4.9 45.1 ± 4.0 p ¼ 1.000 p ¼ 1.000 p ¼ 0.251 BMI (kg/m2) 20.9 ± 2.2 21.6 ± 1.9 21.1 ± 1.3 p ¼ 0.818 p ¼ 1.000 p ¼ 1.000 BMD (mg/cm2) Vertebrae (L2-L4) 972.1 ± 82.8 921.1 ± 92.5 899.1 ± 136.4 p ¼ 0.540 p ¼ 0.162 p ¼ 1.000 Total hip 978.8 ± 91.9 939.1 ± 105.5 916.7 ± 127.5 p ¼ 0.917 p ¼ 0.320 p ¼ 1.000 Femoral neck 744.6 ± 91.5 725.2 ± 95.9 721.6 ± 85.3 p ¼ 1.000 p ¼ 1.000 p ¼ 1.000 Clinical laboratory test results Serum creatinine (mg/dL) 0.63 ± 0.09 0.59 ± 0.06 0.66 ± 0.09 p ¼ 0.213 p ¼ 1.000 p ¼ 0.078 TRACP-5b (mU/dL) 580.8 ± 156.3 613.8 ± 182.6 624.4 ± 164.4 p ¼ 1.000 p ¼ 1.000 p ¼ 1.000

BMD: bone mineral density; BMI: body mass index; EL: elcatonin; L: lumbar; MIN: minodronic acid hydrate; SD: standard deviation; TRACP-5b: tartrate-resistant acid phosphatase 5b.

Please cite this article in press as: Tanaka S, et al., Effectiveness of monotherapy and combined therapy with calcitonin and minodronic acid hydrate, a bisphosphonate, for early treatment in patients with new vertebral fractures: An open-label, randomized, parallel-group study, Journal of Orthopaedic Science (2017), http://dx.doi.org/10.1016/j.jos.2016.12.021 4 S. Tanaka et al. / Journal of Orthopaedic Science xxx (2017) 1e6

Table 2 Comparison of VAS scores and TRACP-5b levels between groups.

Variable Observation time point EL group n ¼ 16 MIN group n ¼ 17 EL þ MIN group n ¼ 18 Between-group comparison (Bonferroni correction)

EMM 95% CI EMM 95% CI EMM 95% CI EL vs MIN EL vs EL þ MIN MIN EL þ MIN

VAS Measurement Baseline 93.1 [88.2, 98.1] 84.1 [79.3, 88.9] 90.6 [85.9, 95.2] p ¼ 0.035* p ¼ 1.000 p ¼ 0.177 (mm) 1 week 68.1 [62.3, 73.9] 74.7 [69.1, 80.4] 61.1 [55.6, 66.6] p ¼ 0.329 p ¼ 0.253 p ¼ 0.003** 2 weeks 55.6 [49.9, 61.3] 65.3 [59.7, 70.8] 50.0 [44.6, 55.4] p ¼ 0.055 p ¼ 0.470 p ¼ 0.001** 3 weeks 41.9 [36.6, 47.2] 55.3 [50.2, 60.4] 33.9 [28.9, 38.9] p ¼ 0.002** p ¼ 0.095 p < 0.001*** 4 weeks 32.5 [27.8, 37.2] 48.2 [43.7, 52.8] 28.3 [23.9, 32.8] p < 0.001*** p ¼ 0.603 p < 0.001*** 2 months 21.9 [17.2, 26.5] 33.5 [29.0, 38.1] 20.6 [16.2, 24.9] p ¼ 0.002** p ¼ 1.000 p < 0.001*** 3 months 13.1 [9.1, 17.1] 28.2 [24.4, 32.1] 14.4 [10.7, 18.2] p < 0.001*** p ¼ 1.000 p < 0.001*** 6 months 10.0 [5.5, 14.5] 17.6 [13.3, 22.0] 11.1 [6.8, 15.4] p ¼ 0.055 p ¼ 1.000 p ¼ 0.110 TRACP-5b Measurement Baseline 580.8 [496.2, 665.3] 613.8 [531.7, 695.8] 624.4 [544.6, 704.1] p ¼ 1.000 p ¼ 1.000 p ¼ 1.000 (mU/dL) 2 weeks 524.8 [459.8, 589.7] 360.5 [297.5, 423.5] 369.7 [308.5, 431.0] p ¼ 0.002** p ¼ 0.003** p ¼ 1.000 4 weeks 421.6 [369.8, 473.3] 340.1 [289.9, 390.3] 292.1 [243.4, 340.9] p ¼ 0.083 p ¼ 0.002** p ¼ 0.522 3 months 400.3 [349.9, 450.6] 273.7 [224.8, 322.5] 274.4 [227.0, 321.8] p ¼ 0.002** p ¼ 0.002** p ¼ 1.000 6 months 380.7 [343.2, 418.2] 226.7 [190.3, 263.1] 216.8 [181.4, 252.2] p < 0.001*** p < 0.001*** p ¼ 1.000

BMD: bone mineral density; BMI: body mass index; CI: confidence interval; EL: elcatonin; EMM: Estimated Marginal Means; MIN: minodronic acid hydrate; SD: standard deviation; TRACP-5b: tartrate-resistant acid phosphatase 5b. *p< 0.05, ** p < 0.01, *** p < 0.001.

abPercent change in Percent change in cPercent change in L2-L4 BMD total hip BMD femoral neck BMD (%) (%) (%) 12 8 12

10 6 10 *** ** ** 8 *** 4 8 **

6 2 6

4 0 4

2 2 2 Estimated marginal means Estimated marginal means Estimated marginal means

0 -4 0

-2 -6 -2 EL MIN EL+MIN EL MIN EL+MIN EL MIN EL+MIN

Fig. 1. Percent change in bone mineral density (BMD) from baseline. EL, elcatonin; MIN, minodronic acid hydrate. *: p < 0.05, **: p < 0.01, ***: p < 0.001. Vertical bars represent standard deviations.

Both EL and MIN are known to promote the inhibition of bone bone can also be expected. The improvement of AHA parameters, resorption, however, the mechanism underlying these additive SM and CSMI, in the combination therapy group appeared to effects of combination therapy remains unknown. Although Hagino corroborate not only the inhibition of bone resorption but also the et al. reported an increase of about 5% of lumbar BMD within 24 maintenance of load stimulus [17]. Although it was reported that weeks by MIN administration [13], the present study demonstrated nitrogen-containing bisphosphonates such as MIN induce osteo- only 2.06% increase in lumbar BMD. Therefore, there was the pos- clast apoptosis and inhibit the formation of an acidic environment, sibility that the effects of MIN were not fully demonstrated. One which consequently reduces transient receptor potential vanilloid- reason for this is that this study was conducted from August to 1-mediated pain stimulation [18,19], the pain inhibiting effect of March in Hokkaido, a region with plenty of snow and less sunshine MIN was hidden by that of EL and was not visible in this study. (daylight), while subjects in the study of Hagino et al. were given an For the patient with an incident vertebral fracture, suffering adequate amount of vitamin D and calcium. In addition, it was re- from sever osteoporosis, the introduction of bone formation- ported that calcitonin increased an active form of vitamin D [14]. promoting teriparatide should be considered for the purpose of Another reason of this was that EL also possesses analgesic actions, preventing secondary fractures and for avoiding non-union at the therefore the patient's QOL and ADL are maintained, or even fracture site. However, this drug is expensive and causes queasy improved, allowing them to avoid pain-induced immobilization side effects as well as a limited duration of administration. A pa- [15,16]. This helps prevent the development of disuse syndrome tient's eligibility for receiving teriparatide, including the timing of and its negative effects. Since the pain inhibiting-effect of EL pre- administration, must be assessed carefully, and at the present time, vented a decline in ADL, this may have led to the maintenance of bisphosphonates are still considered to be the primary method of load stimulus to the bone. Consequently, a positive effect of EL on preventing osteoporotic fractures. For early improvement of ADL-

Please cite this article in press as: Tanaka S, et al., Effectiveness of monotherapy and combined therapy with calcitonin and minodronic acid hydrate, a bisphosphonate, for early treatment in patients with new vertebral fractures: An open-label, randomized, parallel-group study, Journal of Orthopaedic Science (2017), http://dx.doi.org/10.1016/j.jos.2016.12.021 S. Tanaka et al. / Journal of Orthopaedic Science xxx (2017) 1e6 5

a Percent change in buckling ratio b Percent change in section modulus c Percent change in (BR) (SM) cross-sectional moment of inertia (%) (%) (%) (CSMI) 8 28 24

* 4 24 * 20

** 0 20 16 **

-4 16 12

-8 12 8

-12 8 4 Estimated marginal means Estimated marginal means Estimated marginal means

-16 4 0

-20 0 -4 ELMIN EL+MIN ELMIN EL+MIN ELMIN EL+MIN

Fig. 2. Percent change in advanced hip assessment from baseline. EL, elcatonin; MIN, minodronic acid hydrate. *: p < 0.05, **: p < 0.01, ***: p < 0.001. Vertical bars represent standard deviations. related factors such as pain alleviation, the introduction of osteo- [4] Kaptoge S, Beck TJ, Reeve J, Stone KL, Hillier TA, Cauley JA, Cummings SR. porosis treatment, prompt increases in BMD, and improved bone Prediction of incident hip fracture risk by femur geometry variables measured by hip structural analysis in the study of osteoporotic fractures. J Bone Miner structure, combination therapy with calcitonin and bisphospho- Res 2008 Dec;23(12):1892e904. nates appears to be an effective treatment for osteoporosis patients [5] Fujiwara S, Kasagi F, Masunari N, Naito K, Suzuki G, Fukunaga M. Fracture with new vertebral fractures who are considered not in a serious prediction from bone mineral density in Japanese men and women. J Bone Miner Res 2003 Aug;18(8):1547e53. condition. [6] Hagino H, Nakamura T, Fujiwara S, Oeki M, Okano T, Teshima R. Sequential In conclusion, we administered EL þ MIN combination therapy change in quality of life for patients with incident clinical fractures: a pro- to patients with new vertebral fractures who visited our outpatient spective study. Osteoporos Int 2009 May;20(5):695e702. [7] Shiraki M, Kuroda T, Shiraki Y, Aoki C, Sasaki K, Tanaka S. Effects of bone clinic with the main complaint of acute lower back pain. We found mineral density of the lumbar spine and prevalent vertebral fractures on the that, while EL þ MIN alleviated pain similar to only the use of EL risk of immobility. Osteoporos Int 2010 Sep;21(9):1545e51. and inhibited bone resorption similar to that of the use of MIN, this [8] Gehlbach S, Saag KG, Adachi JD, Hooven FH, Flahive J, Boonen S, Chapurlat RD, e Compston JE, Cooper C, Díez-Perez A, Greenspan SL, LaCroix AZ, Netelenbos JC, combination therapy more greatly increased the BMD of the L2 L4 Pfeilschifter J, Rossini M, Roux C, Sambrook PN, Silverman S, Siris ES, vertebrae and femoral neck, it also improved SM and CSMI of AHA Watts NB, Lindsay R. Previous fractures at multiple sites increase the risk for more than in each of the monotherapy groups. subsequent fractures: the global longitudinal study of osteoporosis in women. J Bone Miner Res 2012 Mar;27(3):645e53. [9] Lindsay R, Silverman SL, Cooper C, Hanley DA, Barton I, Broy SB, Licata A, Conflict of interest Benhamou L, Geusens P, Flowers K, Stracke H, Seeman E. Risk of new vertebral fracture in the year following a fracture. JAMA 2001 Jan;285(3):320e3. [10] Ogawa K, Hori M, Takao R, Sakurada T. Effects of combined elcatonin and Shinya Tanaka has received lecture fees from Asahi Kasei alendronate treatment on the architecture and strength of bone in ovariec- Pharma, Chugai Pharmaceutical, Daiichi Sankyo, DePuy Synthes tomized rats. J Bone Miner Metab 2005 Sep;23(5):351e8. Japan, Eisai, Eli Lilly Japan, Taisho Toyama Pharmaceutical and Teijin [11] Hongo M, Miyakoshi N, Kasukawa Y, Ishikawa Y, Shimada Y. Additive effect of elcatonin to risedronate for chronic back pain and quality of life in post- Pharma. Akira Yoshida has received lecture fees from Asahi Kasei menopausal women with osteoporosis: a randomized controlled trial. J Bone Pharma, Chugai Pharmaceutical and Eisai. Manabu Ito has received Miner Metab 2015 Jul;33(4):432e9. lecture fees from Asahi Kasei Pharma. [12] Takakuwa M, Iwamoto J. Elcatonin in combination with risedronate is more effective than risedronate alone for relieving back pain in postmenopausal women with osteoporosis. Biol Pharm Bull 2012;35(7):1159e65. Acknowledgment [13] Hagino H, Shiraki M, Fukunaga M, Nakano T, Takaoka K, Ohashi Y, Nakamura T, Matsumoto T. Three years of treatment with minodronate in patients with postmenopausal osteoporosis. J Bone Miner Metab 2012 This study was supported by Asahi Kasei Pharma. Jul;30(4):439e46. [14] Tanko LB, Bagger YZ, Alexandersen P, Devogelaer JP, Reginster JY, Chick R, Olson M, Benmammar H, Mindeholm L, Azria M, Christiansen C. Safety and References efficacy of a novel salmon calcitonin (sCT) technology-based oral formulation in healthy postmenopausal women: acute and 3-month effects on biomarkers e [1] Orimo H, Nakamura T, Hosoi T, Iki M, Uenishi K, Endo N, Ohta H, Shiraki M, of bone turnover. J Bone Miner Metab 2004 Sep;19(9):1531 8. Sugimoto T, Suzuki T, Soen S, Nishizawa Y, Hagino H, Fukunaga M, Fujiwara S. [15] Knopp JA, Diner BM, Blitz M, Lyritis GP, Rowe BH. Calcitonin for treating acute Japanese 2011 guidelines for prevention and treatment of osteopor- pain of osteoporotic vertebral compression fractures: a systematic review of e osiseexecutive summary. Arch Osteoporos 2012 Dec;7(1e2):3e20. randomized, controlled trials. Osteoporos Int 2005 Oct;16(10):1281 90. [2] Orimo H, Nakamura T, Fukunaga M, Ohta H, Hosoi T, Uemura Y, Kuroda T, [16] Knopp-Sihota JA, Newburn-Cook CV, Homik J, Cummings GG, Voaklander D. Miyakawa N, Ohashi Y, Shiraki M, A-TOP (Adequate Treatment of Osteopo- Calcitonin for treating acute and chronic pain of recent and remote osteo- rosis) research group. Effects of alendronate plus alfacalcidol in osteoporosis porotic vertebral compression fractures: a systematic review and meta- e patients with a high risk of fracture: the Japanese Osteoporosis Intervention analysis. Osteoporos Int 2012 Jan;23(1):17 38. Trial (JOINT)-02. Curr Med Res Opin 2011 Jun;27(6):1273e84. [17] Heinonen A, Mantynen J, Kannus P, Uusi-Rasi K, Nikander R, Kontulainen S, [3] Genant HK, Jergas M, Palermo L, Nevitt M, Valentin RA, Black D, Cummings SR. Sievanen H. Effects of high-impact training and detraining on femoral neck Comparison of semiquantitative visual and quantitative morphometric structure in premenopausal women: a hip structural analysis of an 18-month assessment of prevalent and incident vertebral fractures in osteoporosis. randomized controlled exercise intervention with 3.5-year follow-up. Physi- e J Bone Miner Res 1996;11(7):984e96. other Can 2012;64(1):98 105.

Please cite this article in press as: Tanaka S, et al., Effectiveness of monotherapy and combined therapy with calcitonin and minodronic acid hydrate, a bisphosphonate, for early treatment in patients with new vertebral fractures: An open-label, randomized, parallel-group study, Journal of Orthopaedic Science (2017), http://dx.doi.org/10.1016/j.jos.2016.12.021 6 S. Tanaka et al. / Journal of Orthopaedic Science xxx (2017) 1e6

[18] Kakimoto S, Nagakura Y, Tamura S, Watabiki T, Shibasaki K, Tanaka S, Mori M, [19] Nagae M, Hiraga T, Yoneda T. Acidic microenvironment created by osteoclasts Sasamata M, Okada M. Minodronic acid, a third-generation bisphosphonate, causes bone pain associated with tumor colonization. J Bone Miner Metab antagonizes purinergic P2X(2/3) receptor function and exerts an analgesic 2007 Mar;25(2):99e104. effect in pain models. Eur J Pharmacol 2008 Jul;589(1e3):98e101.

Please cite this article in press as: Tanaka S, et al., Effectiveness of monotherapy and combined therapy with calcitonin and minodronic acid hydrate, a bisphosphonate, for early treatment in patients with new vertebral fractures: An open-label, randomized, parallel-group study, Journal of Orthopaedic Science (2017), http://dx.doi.org/10.1016/j.jos.2016.12.021