Forteo (Teriparatide) AHM

Forteo (Teriparatide) AHM Clinical Indications Forteo (Teriparatide) is considered medically necessary if criteria are met for any 1 or more of the following Treatment of post-menopausal women with osteoporosis who are at high risk for fracture when ALL of the following criteria are met: [A] The T score of their bone mineral density is 2.5 or more standard deviations below the mean value (i.e., T score is less than -2.5) (a T score of -1.0 to -2.5 is classified as osteopenia, while a T score of -1.0 or higher is considered normal) [B] Patients who had a previous osteoporotic vertebral compression fracture and who have failed* a treatment course with a bisphosphonate or a selective estrogen receptor modulator (SERM), or are intolerant to the side effects of bisphosphonates/serms or for whom oral bisphosphonate therapy is contraindicated (e.g., due to inability to swallow, or inability to remain in an upright position after oral bisphosphonate administration for the required length of time). Treatment of men with primary or hypogonadal osteoporosis who are at high risk for fracture when ALL of the following criteria are met: The T score of their bone mineral density is 2.5 or more standard deviations below the mean value (i.e., T score is less than -2.5) (a T score of -1.0 to -2.5 is classified as osteopenia, while a T score of -1.0 or higher is considered normal) Patients who have had a previous osteoporotic vertebral compression fracture and who have failed a treatment course with a bisphosphonate, or are intolerant to the side effects of bisphosphonates [C] or for whom oral bisphosphonate therapy is contraindicated (e.g., due to inability to swallow, or inability to remain in an upright position after oral bisphosphonate administration for the required length of time). Daily injection of teriparatide (Forteo) is considered medically necessary for the treatment of adults with glucocorticoid-induced osteoporosis (T score of their BMD is 2.5 or more standard deviations below the mean value (i.e., T score is less than -2.5) (a T score of -1.0 to -2.5 is classified as osteopenia, while a T score AC-AEFOR082011 Page 1 of 17

of -1.0 or higher is considered normal) [D] ), when ALL of the following criteria are met: Members are being treated with sustained long-term glucocorticoid therapy (i.e., a mean daily dose of 5 mg or more of prednisone or its equivalent for 3 or more consecutive months) Members are at high-risk for fractures (e.g., those who have had an osteoporotic fracture, or have certain risk factors for fracture [E] ), and have failed [F] or are unable to tolerate 2 oral bisphosphonates (e.g., alendronate [Fosamax], risedronate [Actonel]), or for whom oral bisphosphonate therapy is contraindicated (e.g., due to inability to swallow, or inability to remain in an upright position after oral bisphosphonate administration for the required length of time). Current role remains uncertain. Based on review of existing evidence, there are currently no clinical indications for this technology. See Inappropriate Uses for more detailed analysis of the evidence base. Forteo is considered investigational for orthopedic uses (e.g., articular cartilage repair and fracture repair), osteogenesis imperfecta, osteoporosis associated with inflammatory bowel disease hungry bone syndrome, for reducing pedicle screw loosening following spinal fusion and for all other indications because its effectiveness for these indications has not been established. Note: Therapy for more than 2 years duration is considered investigational as the effects of long-term treatment with teriparatide are not known at this time. Evidence Summary Background Approximately 10 million Americans (80% of them women) suffer from osteoporosis, which may lead to an increased risk of spine, wrist, and hip fractures. For postmenopausal women, age, personal or family history of fracture, Asian or Hispanic heritage, smoking, and cortisone use have been associated with significantly increased likelihood of osteoporosis; while higher body mass index (BMI), African American heritage, estrogen or diuretic use, and exercise have been associated with significantly decreased likelihood of osteoporosis (Siris, et al., 2001). Furthermore, Wu and colleagues (2002) reported that any fracture (unrelated to motor vehicle accidents) sustained between the ages of 20 and 50 years is associated with increased risk of fractures after the age of 50 years in women. Although osteoporosis is usually considered a disease of AC-AEFOR082011 Page 2 of 17

women, up to 20% of vertebral fractures and 30% of hip fractures occur in men. Risk factors for osteoporotic fractures in men include low BMI, smoking, high alcohol consumption, corticosteroid therapy, physical inactivity, and diseases that predispose to low bone mass (Eastell, et al., 1998). However, the exact mechanism of bone loss remains unknown in primary male osteoporosis (Legrand, et al., 2001). Bone mineral density (BMD) is useful in the diagnosis of osteoporosis. It is usually provided as the T score -- the number of standard deviations (SDs) the BMD falls below or above the mean value in a reference population (young, healthy adults). The World Health Organization (WHO) osteoporosis diagnostic classification assessment (1994) defines osteoporosis as a T score of 2.5 or more SDs below the mean (i.e., less than -2.5). Osteopenia is defined as a T score of -1.0 to -2.5 and a T score of -1.0 or higher is considered normal. It should be noted that a male database should be used for diagnosing osteoporosis in men. Body (2002) stated that although hormone replacement therapy (HRT) is still considered as the mainstay for the prevention and the treatment of post-menopausal osteoporosis, there are several controversies regarding HRT. Recent studies have challenged the assumption that HRT conveys real long-term benefits. Raloxifene or other selective estrogen receptor modulators should progressively replace HRT in elderly women. Bisphosphonates have been shown to be effective in the treatment of osteoporosis. Alendronate (Fosamax) and risedronate (Actonel) have been the most extensively studied bisphosphonates under clinical trials conditions. Both drugs can lower the risk of vertebral and hip fractures by 25 to 50%. However, oral bisphosphonates exhibit gastrointestinal toxicity and strict adherence to constraining therapeutic schemes is mandatory. Newer more potent bisphosphonates, such as oral ibandronate and intravenous zoledronic acid (Zometa), which will allow much less frequent administration, are currently being investigated (Reid, et al., 2002). Moreover, boneforming agents (e.g., teriparatide) provide another therapeutic option for the treatment of severe osteoporosis. Teriparatide (Forteo) is the first approved medication for the treatment of osteoporosis that stimulates new bone formation. It is administered by once-daily subcutaneous injection in the thigh or abdomen. The recommended dosage is 20 mcg/day. Teriparatide is a portion of human parathyroid hormone (PTH 1-34), which is the primary regulator of calcium and phosphate metabolism in bones. Daily injections of teriparatide stimulate new bone formation resulting in increased bone mineral density (BMD). Clinical studies showed that teriparatide lowered the risk of vertebral and non-vertebral fractures in postmenopausal women and increased BMD in men with primary or hypogonadal osteoporosis when compared to patients who received only calcium and vitamin D supplementation. Rehman, et al. (2003) examined whether daily treatment with PTH 1-34 for 1 year was associated with a change in vertebral cross-sectional area, or vertebral size in postmenopausal women (n = 51), as measured by serial quantitative computed tomography scans. The authors found that daily treatment with PTH 1-34 for 1 year increased vertebral size as measured by vertebral cross-sectional area and this increase was maintained after PTH 1-34 was discontinued. Furthermore, Marcus, et al. (2003) reported AC-AEFOR082011 Page 3 of 17

that teriparatide offers clinical benefit to patients across a broad range of age and disease severity. Body and co-workers (2002) compared the effects of teriparatide and alendronate on BMD, non-vertebral fracture incidence, and bone turnover in 146 post-menopausal women with osteoporosis. Women were randomized to either once-daily subcutaneous injections of teriparatide 40 mcg plus oral placebo (n = 73) or oral alendronate 10 mg plus placebo injection (n = 73). Median duration of treatment was 14 months. At 3 months, teriparatide increased lumbar spine BMD significantly more than did alendronate. Lumbar spine-bmd increased by 12.2% in the teriparatide group and 5.6% in the alendronate group. Teriparatide increased femoral neck BMD and total body bone mineral significantly more than did alendronate, but BMD at the one-third distal radius decreased, compared with alendronate. Non-vertebral fracture incidence was significantly lower in the teriparatide group than in the alendronate group. Both treatments were well tolerated despite transient mild asymptomatic hypercalcemia with teriparatide treatment. These investigators concluded that teriparatide, a bone-forming agent, increased BMD at most sites and decreased non-vertebral fractures more than alendronate. However, more comparative studies are needed to validate this finding. Orwoll, et al. (2003) studied the effects of teriparatide on bone density in men with osteoporosis: 437 men with spine or hip BMD more than 2 standard deviations below the young adult male mean were randomized to three groups: (i) daily injections of placebo, (ii) teriparatide 20 mcg, or (iii) teriparatide 40 mcg. All subjects also received supplemental calcium and vitamin D. The study was stopped after a median duration of 11 months because of a finding of osteosarcomas in rats in routine toxicology studies. Biochemical markers of bone formation increased early in the course of therapy and were followed by increases in indices of osteoclastic activity. Spine BMD was significantly greater than in placebo subjects after 3 months of teriparatide therapy, and by the end of therapy it was increased by 5.9% (20 mcg) and 9.0% (40 mcg) above baseline. Femoral neck BMD increased 1.5% (20 mcg) and 2.9% (40 mcg), and whole body bone mineral content increased 0.6% (20 mcg) and 0.9% (40 mcg) above baseline in the teriparatidetreated subjects. There was no change in radial BMD in the teriparatide-treated groups. Bone mineral density responses to teriparatide were similar regardless of gonadal status, age, baseline BMD, body mass index, smoking, or alcohol intake. Subjects experienced expected changes in mineral metabolism. Adverse events were similar in the placebo and 20-mcg groups, but more frequent in the 40-mcg group. This study shows that teriparatide treatment results in an increase in BMD and is a potentially useful therapy for osteoporosis in men. Most adverse events reported in association with teriparatide in clinical trials were mild and included nausea, dizziness, and leg cramps. During the clinical trials, early discontinuation due to adverse events occurred in 5.6 and 7.1% of patients in the control and treatment groups, respectively. Although not observed in human clinical trials, teriparatide is associated with development of osteosarcomas in animal studies. In a review on the use of intermittent human PTH as a treatment for osteoporosis Deal (2004) explained that patients who have Paget's disease, prior radiation therapy to the skeleton, as well as children and young adults with open epiphyses, are at higher risk for AC-AEFOR082011 Page 4 of 17

osteosarcoma and should not be given PTH. Patients with hypercalcemia and hyperparathyroidism also should not receive the drug. Forteo's product labeling carries a black box safety warning, which highlights the concern over the association between the drug and osteosarcomas in laboratory rats. Because individuals with growing bones (namely children and adolescents with open epiphyses), persons with unexplained elevations in alkaline phosphatase, patients with prior external beam or implant irradiation of the skeleton, and patients with Paget's disease of the bone have a higher risk for developing osteosarcoma, the black box warning states that it is important that teriparatide not be used in these groups. Furthermore, the product labeling states that individuals with hypercalcemia, women who are pregnant or nursing, or those who have ever been diagnosed with bone cancer or other cancers that have metastasized to the bones, should not use teriparatide. According to the product labeling, because the long-term effectiveness and safety of teriparatide treatment are not known at this time, therapy for more than 2 years is not recommended. The Canadian Coordinating Office of Health Technology Assessment (Shulka, 2003) reached the following conclusions about teriparatide: "Although placebo-controlled trials show that teriparatide can reduce fractures, there is little information on its efficacy compared to available alternatives. In the United States, the Food and Drug Administration (FDA) highlighted concerns about teriparatide's carcinogenic effects in rats. Company-sponsored studies have been voluntarily stopped Because of safety concerns and the lack of efficacy and effectiveness data, it is difficult to define teriparatide's role in the treatment of osteoporosis. This is compounded by the possible long-term antagonizing effect of bisphosphonates on teriparatide's bone-forming properties." Combination therapy with teriparatide or parathyroid hormone (1-84) and an antiresorptive agent has not been proven to offer advantages over the use of parathyroid hormone or an anti-resorptive agent alone for osteoporosis. Bilezikian and Rubin (2006) discussed the use of anabolic skeletal therapy for the treatment of post-menopausal and other forms of osteoporosis. The authors stated that the only anabolic skeletal agent currently available is teriparatide. Teriparatide improves bone quality by actions on bone turnover, bone density, bone size, and micro-architecture. In post-menopausal women with osteoporosis, teriparatide reduces the incidence for vertebral and non-vertebral fractures. In individuals who have been treated previously with an anti-resorptive agent (e.g., estrogen and bisphosphonates), the subsequent actions of teriparatide on bone density are delayed transiently if bone turnover is markedly suppressed. The authors argued that combination therapy with teriparatide or PTH (1-84) and an anti-resorptive does not appear, at this time, to offer advantages over the use of PTH or an antiresorptive alone. In a randomized, open-labeled clinical study, Matsumoto, et al. (2006) examined the safety and effectiveness of nasal hpth(1-34) spray in subjects with osteoporosis. A total of 90 osteoporotic subjects aged 52 to 84 years (mean of 66.5 years) were randomly assigned to receive either 250 mcg (PTH250, n = 31), 500 mcg (PTH500, n = 30), or 1,000 mcg (PTH1000, n = 29) of daily nasal hpth(1-34) spray for 3 months. All subjects received daily supplements of 300 mg calcium and 200 IU vitamin D(3). Daily nasal AC-AEFOR082011 Page 5 of 17

hpth(1-34) spray for 3 months increased lumbar bone mineral density (L-BMD) in a dose-dependent manner, and the PTH1000 group showed a 2.4 % increase in L-BMD from baseline. Only the 1,000-mcg dose produced consistent and statistically significant changes in markers of bone turnover; after 3 months, median serum type I procollagen N- propeptide (PINP) and osteocalcin increased 14.8 % and 19.4 % from baseline, while urinary type I collagen N-telopeptide (NTX) decreased 16.4 %. Seven subjects developed transient hypercalcemia at 3 hours after nasal hpth(1-34) spray, but none of the subjects developed sustained hypercalcemia. The authors concluded that these findings showed that nasal hpth(1-34) spray is safe and well-tolerated and can rapidly increase L-BMD. They noted that the results warrant further studies to examine its long-term effectiveness on bone mass and fractures. In July 2009, the FDA expanded the indications for teriparatide to include adults with a high risk for fracture related to glucocorticoid-induced osteoporosis. The FDA's decision was based on data from an 18-month randomized, double-blind, controlled clinical trial that compared teriparatide with alendronate in 428 women and men with osteoporosis (aged 22 to 89 years) who had received sustained glucocorticoid therapy. Sustained glucocorticoid therapy was defined as a mean daily dose of 5 mg or more of prednisone or its equivalent for at least 3 months. A total of 214 patients received 20 mcg of teriparatide once-daily, and 214 received 10 mg of alendronate once-daily. The primary outcome was the change in BMD at the lumbar spine. Secondary outcomes included changes in BMD at the total hip and in markers of bone turnover, the time to changes in BMD, the incidence of fractures, and safety. At the last measurement, the mean (+/- SE) BMD at the lumbar spine had increased more in the teriparatide group than in the alendronate group (7.2 +/- 0.7 % versus 3.4 +/- 0.7 %, p < 0.001). A significant difference between the groups was reached by 6 months (p < 0.001). At 12 months, BMD at the total hip had increased more in the teriparatide group. Fewer new vertebral fractures occurred in the teriparatide group than in the alendronate group (0.6 % versus 6.1%, p = 0.004); the incidence of non-vertebral fractures was similar in the two groups (5.6% versus 3.7%, p = 0.36). Significantly more patients in the teriparatide group had at least one elevated measure of serum calcium. The authors concluded that among patients with osteoporosis who were at high risk for fracture, BMD increased more in patients receiving teriparatide than in those receiving alendronate (Saag, et al., 2007). Losada, et al. (2009) compared teriparatide versus alendronate on BMD in Hispanic (n=61) and non-hispanic (n = 367) patients with glucocorticoid-induced osteoporosis. Data from the 18-month study from all patients (n = 428) in a double-blind trial of teriparatide (20 mcg per day) and alendronate (10 mg per day) who had taken glucocorticoids for 3 or more months were analyzed (Saag, et al., 2007). At the last measurement, the mean (+/- SE) BMD at the lumbar spine in the Hispanic cohort had increased more in the teriparatide versus alendronate group (9.8% +/- 1.7% versus 4.2% + /-1.4%; p < 0.001) and total hip BMD (5.9% +/- 1.6% versus 3% +/- 1.3%, p < 0.001), with no significant difference between groups at the femoral neck (4.3% +/ -2.2% versus 2.0% +/- 1.8%, p = 0.228). Within each treatment group, the BMD responses were not significantly different in the Hispanic versus non-hispanic cohort. The number of patients reporting one or more adverse event was not significantly different between AC-AEFOR082011 Page 6 of 17

treatments in either cohort, with more patients reporting nausea in the teriparatide group. The authors concluded that teriparatide was more efficacious than alendronate in increasing BMD in Hispanic and non-hispanic patients with glucocorticoid-induced osteoporosis and that both treatments were generally well tolerated. Rodríguez-Bores, et al. (2007) stated that inflammatory bowel disease (IBD) has been associated with an increased risk of osteoporosis and osteopenia and epidemiological studies have reported an increased prevalence of low bone mass in patients with IBD. Certainly, genetics play an important role, along with other factors such as systemic inflammation, malnutrition, hypogonadism, glucocorticoid therapy in IBD and other lifestyle factors. At a molecular level the pro-inflammatory cytokines that contribute to the intestinal immune response in IBD are known to enhance bone resorption. There are genes influencing osteoblast function and it is likely that LRP5 may be involved in the skeletal development. Also the identification of vitamin D receptors (VDRs) and some of its polymorphisms have led to consider the possible relationships between them and some autoimmune diseases and may be involved in the pathogenesis through the exertion of its immunomodulatory effects during inflammation. These researchers found that there is increasing evidence for the integration between systemic inflammation and bone loss likely mediated via receptor for activated nuclear factor kappa-b (RANK), RANKligand, and osteoprotegerin, proteins that can affect both osteoclastogenesis and T-cell activation. Although glucocorticoids can reduce mucosal and systemic inflammation, they have intrinsic qualities that negatively impact on bone mass. It is still controversial if all IBD patients should be screened, especially in patients with pre-existing risk factors for bone disease. Available methods to measure BMD include single energy x-ray absorptiometry, dual energy x-ray absorptiometry, quantitative computed tomography, radiographical absorptiometry, and ultrasound. Dual energy x-ray absorptiometry is the establish method to determine BMD, and routinely is measured in the hip and the lumbar spine. There are several treatments options that have proven their effectiveness, while new emergent therapies such as calcitonin and teriparatide among others remain to be assessed. In a review on bisphosphonates and other new therapeutic agents for the treatment of osteogenesis imperfecta (OI), Yamashita (2009) stated that OI is a genetic disorder characterized by fragile bone and reduced BMD. Cyclic intravenous pamidronate is now the standard treatment for moderate-to-severe forms of OI, however clinical studies are not yet sufficient to conclude appropriate annual dose and ideal duration of therapy at present time. Oral alendronate is also effective in milder forms of OI. Zoledronic acid has undergone international multi-center clinical trials to examine effectiveness and longterm side effects including osteonecrosis of the jaw. Teriparatide and denosumab have the potential for managing patients with OI. Gene therapy and stem cell are currently being actively investigated and may become clinically applicable in the near future. Appendix Guidance from the National Institute for Health and Clinical Excellence (2011) recommends teriparatide as an alternative treatment option for the secondary prevention of osteoporotic fragility fractures in postmenopausal women: 1) who are unable to take alendronate and either risedronate or etidronate, or have a contraindication to or are AC-AEFOR082011 Page 7 of 17

intolerant of alendronate and either risedronate or etidronate, or who have a contraindication to, or are intolerant of strontium ranelate, and 2) who have had an unsatisfactory response to treatment with alendronate, risedronate or etidronate and who are 65 years or older and have a T-score of -4.0 SD or below, or a T-score of -3.5 SD or below plus more than two fractures, or who are aged 55-64 years and have a T-score of -4 SD or below plus more than two fractures. For the purposes of this guidance, independent clinical risk factors for fracture are parental history of hip fracture, alcohol intake of 4 or more units per day, and rheumatoid arthritis. The guidance defines intolerance to bisphosphonates as persistent upper gastrointestinal disturbance that is sufficiently severe to warrant discontinuation of treatment, and that occurs even though the instructions for administration have been followed correctly. The guidance defines intolerance to strontium ranelate as persistent nausea or diarrhea, either of which warrants discontinuation of treatment. An unsatisfactory response is defined as occurring when a woman has another fragility fracture despite adhering fully to treatment for 1 year and there is evidence of a decline in BMD below her pre-treatment baseline. The Australian Pharmaceutical Benefits Scheme (2009) has listed teriparatide for severe established osteoporosis in people at very high risk of fracture who develop one or more new symptomatic fractures despite at least 12 months of continuous antiresorptive therapy. Treatment with teriparatide is limited to a total of 18 months to reduce the risk of osteosarcoma. The PBS defines a vertebral fracture as a 20% or greater reduction in height of an anterior or mid-portion vertebral body relative to the posterior height of that body, or a 20% or greater reduction in any vertebral height compared with vertebral height above or below the affected vertebral body. For purposes of this policy, antiresorptive doses were defined as: alendronate 10 mg daily or 70 mg weekly, risedronate 5 mg daily or 35 mg weekly, raloxifene 60 mg daily (women only), etidronate 200 mg with calcium carbonate 1.25 g daily, strontium 2 g daily and zoledronic acid 5 mg once a year. If severe intolerance occurs that requires permanent withdrawal of one antiresorptive agent, the PBS requires a trial of an alternative antiresorptive agent so that a minimum of 12 months of continuous therapy is achieved. The Canadian Expert Drug Advisory Committee (CEDAC, 2010) review on the use of teriparatide in severe osteoporosis in women found no randomized controlled trials meeting the Common Drug Review systematic review protocol that evaluated teriparatide in women previously treated with anti-resorptive therapy. The Committee considered the European Study of Forsteo (EUROFORS) and European Forsteo Observational Study (EFOS) studies, both of which included some patients who had received prior antiresorptive therapy, but found that interpretation of data from these studies was limited. The CEDAC stated that, although EUROFORS is a randomized controlled trial, the effects of teriparatide in patients previously receiving anti-resorptive therapy were only evaluated in a subgroup analysis that did not include a comparative group, fracture outcomes were not reported, and all patients had previously been exposed to teriparatide for 12 months. The CEDAC noted that, although EFOS enrolled patients who had an insufficient response or who were intolerant to prior anti-resorptive therapy, it was an AC-AEFOR082011 Page 8 of 17

open-label uncontrolled study and a substantial proportion of patients did not complete the study on treatment. Women who are pregnant or nursing. The Canadian Expert Drug Advisory Committee did not reommend teraparatide for glucocorticoid-induced osteoporosis. CEDAC identified only one double-blind randomized-controlled trial (n =428) evaluating the effects of teriparatide on glucocorticoid-induced osteoporosis. The study found no differences between teraparatide and alendronate for incidence of non-verteral fracture (including hip fracture) or clinical (symptomatic) vertebral fracture. The incidence of radiographic vertebral fractures was statistically significantly lower in the teriparatide group compared with the alendronate group; however, a large proportion of patients were missing radiographic data, reducing confidence in these results. Guidelines from the American Association of Clinical Endocrinologists (Watts, et al. 2012) recommend use teriparatide for patients with very high fracture risk or patients in whom bisphosphonate therapy has failed. They state that teriparatide is contraindicated in patients at increased risk of osteosarcoma (those with Paget disease of bone, open epiphyses, a history of irradiation involving the skeleton, or an unexplained elevation of alkaline phosphatase level of skeletal origin). Teriparatide should also not be administered to patients with primary or any form of secondary untreated or unresolved hyperparathyroidism. Bukata and Puzas (2010) reviewed the current animal and human reports available on the uses of teriparatide in musculoskeletal diseases beyond osteoporosis. In the treatment of osteoporosis, teriparatide works as an anabolic agent stimulating bone formation throughout the skeleton by principally enhancing osteoblast-derived bone formation relative to osteoclast-derived bone resorption. The net effect is increased bone mass. For patients with a fracture, a similar process of increased bone formation is needed transiently at the fracture site for repair. Teriparatide has been investigated in animal models as well as in patients as a potential agent to enhance fracture repair. Furthermore, evidence that teriparatide enhances chondrogenesis has generated interest in using the agent for articular cartilage repair. Research is currently underway to understand the effects teriparatide may have on mesenchymal stem cells, and on other effects that have been reported anecdotally in patients using the drug for osteoporosis care, including the healing of fracture nonunions and a decreased incidence of back pain. In a prospective, randomized, double-blind study, Aspenberg et al (2010) tested the hypothesis that recombinant teriparatide, at the 20 microg dose normally used for osteoporosis treatment or higher, would accelerate fracture repair in humans. Postmenopausal women (45 to 85 years of age) who had sustained a dorsally angulated distal radial fracture in need of closed reduction but no surgery were randomly assigned to 8 weeks of once-daily injections of placebo (n = 34) or teriparatide 20 microg (n = 34) or teriparatide 40 microg (n = 34) within 10 days of fracture. Hypotheses were tested sequentially, beginning with the teriparatide 40 microg versus placebo comparison, using a gatekeeping strategy. The estimated median time from fracture to first radiographical evidence of complete cortical bridging in 3 of 4 cortices was 9.1, 7.4, and 8.8 weeks for placebo and teriparatide 20 microg and 40 microg, respectively (overall p = 0.015). AC-AEFOR082011 Page 9 of 17

There was no significant difference between the teriparatide 40 microg versus placebo groups (p = 0.523). In post-hoc analyses, there was no significant difference between teriparatide 40 microg versus 20 microg (p = 0.053); however, the time to healing was shorter in teriparatide 20 microg than placebo (p = 0.006). The primary hypothesis that teriparatide 40 microg would shorten the time to cortical bridging was not supported. The shortened time to healing for teriparatide 20 microg compared with placebo still may suggest that fracture repair can be accelerated by teriparatide, but this result should be interpreted with caution and warrants further study. In a prospective, controlled, randomized, open-label, 2-year study, Lyritis et al (2010) examined changes in back pain in post-menopausal women with severe osteoporosis who received teriparatide for 24 months or switched at 12 months to raloxifene or no active treatment. A total of 868 post-menopausal women with osteoporosis and a recent fragility fracture wer enrolled in this study. After 12 months of teriparatide (20 microg/day), 507 patients were randomised to further teriparatide (n = 305), raloxifene 60 mg/day (n = 100), or no active treatment (n = 102) for another 12 months (substudy 1); in substudy 2, 199 patients continued teriparatide. All received calcium and vitamin D supplementation. Back pain was self-assessed by patients using a visual analog scale (VAS; 0 to 100 mm). Changes in back pain were analysed using a mixed model for repeated measures. During year 1, back pain decreased from a mean (SD) of 48.9 mm (24.0) at baseline by 11.5 mm (p < 0.001) in the total study population. In substudy 1, mean change in back pain from month 12 (randomization) to 24 months was -2.2, -4.4 and +0.7 mm in the teriparatide (p = 0.076), raloxifene (p = 0.041), and no active treatment groups (p = 0.751). There were no between-group differences from randomization to 18 or 24 months. In a sensitivity analysis excluding patients with low baseline back pain (VAS les than 30 mm), mean change from randomization to endpoint was significant for teriparatide (-3.9 mm, p = 0.006) and raloxifene (-6.3 mm, p = 0.018) groups. Subgroup analyses of 503 patients who received teriparatide for up to 2 years showed that patients with a recent vertebral fracture had a greater decrease in back pain than those without (p < 0.05). Those with and without mild back pain (greater than or equal to 30 mm), and those with and without severe back pain (greater than or equal to 60 mm) at baseline all had a statistically significant reduction in back pain after 24 months (p < 0.05). The authors concluded that teriparatide treatment is associated with significant reductions in back pain regardless of the presence of recent vertebral fracture. Moreover, they stated that these results need to be considered with caution due to the open-label design of the study. Borges et al (2013) noted that satisfactory healing of the osteoporotic fracture is critically important to functional recovery, morbidity, and quality of life. Some therapies for osteoporosis may affect the processes associated with bone repair. For example, bisphosphonates in experimental models are associated with increased callus size and mineralization, reduced callus remodeling, and improved mechanical strength. Local and systemic bisphosphonate treatment may improve implant fixation. No negative impact on fracture healing has been observed, even after major surgery or when administered immediately after fracture. For the osteo-anabolic agent teriparatide, case reports and a AC-AEFOR082011 Page 10 of 17

randomized controlled trial (RCT) have produced mixed results, but they are consistent with a positive impact of teriparatide on fracture healing. Some of the agents currently being developed for osteoporosis, notably sclerostin and DKK1 antibodies have shown a beneficial effect on fracture healing. At this point, therefore, there is no evidence that osteoporosis therapies are detrimental to fracture healing with some promising experimental evidence for positive effects on healing, notably for those agents whose actions are primarily anabolic. Zhang et al (2013) performed a systematic literature review on the use of recombinant PTH in human fracture healing to (i) evaluate the evidence for recombinant PTH in human fracture healing, and (ii) examine if there are notable differences between prior case reports and prospective trials. These researchers performed a literature search in PubMed, EMBASE, Web of Science, and the Cochrane Database of Systematic Reviews for "teriparatide", "PTH (1-84)", "fracture", and "healing". References of retrieved articles were screened for additional studies, and exclusion criteria were applied. Due to the limited publications on the subject, case reports and case series were included in the data analysis. Due to the limited publications on the subject, the data were presented in simple tabular format. The authors concluded that the literature review yielded 16 publications on the use of recombinant PTH in human fracture healing, and 2 RCTs with 1 retrospective subgroup analysis. There continues to be anecdotal evidence for the use of recombinant PTH to enhance fracture healing. There are discrepancies in study design in the RCTs and the majority of case reports; the authors stated that additional prospective studies are warranted. Ohtori and colleagues (2013) stated that failure of fixation caused by loosening of reduce pedicle screws (PSs) in osteoporosis is a problem in spinal surgery. Oral administration of bisphosphonate or intermittent injection of PTH increases bone mass and reduces the risk of osteoporotic vertebral fractures. Although these treatments may play a role in improving bone quality, a clinical study of the effectiveness of bisphosphonate or PTH for reducing PS loosening that addresses the quality of the bone marrow and pedicle cortex has not yet been reported. In a prospective study, these researchers examined the effectiveness of teriparatide or bisphosphonate treatment to reduce PS loosening after instrumented lumbar postero-lateral fusion in post-menopausal women with osteoporosis. A total of 62 women with osteoporosis diagnosed with degenerative spondylolisthesis were divided into 3 groups: (i) a teriparatide group (daily subcutaneous injection of 20 μg of teriparatide, n = 20), (ii) a bisphosphonate group (daily oral administration 2.5 mg of risedronate, n = 20), and (iii) a control group (without medication for osteoporosis, n = 22). All patients underwent decompression and 1- or 2-level instrumented postero-lateral fusion with a local bone graft. Loosening of PSs and surgical outcome were evaluated radiographically, clinically, and by computed tomography 12 months after surgery. At 12-month follow-up, the incidence of PS loosening was 7 % to 13 % in the teriparatide group, 13 % to 26 % in the risedronate group, and 15 % to 25 % in the control group. The incidence of PS loosening in the teriparatide group was significantly lower than that in the risedronate or the control group (p < 0.05). In contrast, the extent of PS loosening in the risedronate group was not significantly different from that in the control group (p > 0.05). The authors concluded that these findings suggested that administration of AC-AEFOR082011 Page 11 of 17

teriparatide increased the quality of the lumbar spine bone marrow and pedicle cortex. These preliminary findings need to be validated by well-designed studies. An UpToDate review on Hungry bone syndrome following parathyroidectomy (Berkoben and Quarles, 2014) does not mention the use of teriparatide as a therapeutic option. References 1. Eastell R, Boyle IT, Compston J, et al. Management of male osteoporosis: Report of the UK Consensus Group. QJM. 1998;91(2):71-92. 2. Siris ES, Miller PD, Barrett-Connor E, et al. Identification and fracture outcomes of undiagnosed low bone mineral density in postmenopausal women: Results from the National Osteoporosis Risk Assessment. JAMA. 2001;286(22):2815-2822. 3. Legrand E, Hedde C, Gallois Y, et al. Osteoporosis in men: A potential role for the sex hormone binding globulin. Bone. 2001;29(1):90-95. 4. National Horizon Scanning Centre (NHSC). Teriparatide for osteoporosis - horizon scanning review. New and Emerging Technology Briefing. Birmingham, UK: NHSC; 2001. 5. Body JJ. Management of primary osteoporosis. Acta Clin Belg. 2002;57(5):277-283. 6. Wu F, Mason B, Horne A, et al. Fractures between the ages of 20 and 50 years increase women's risk of subsequent fractures. Arch Intern Med. 2002;162(1):33-36. 7. Reid IR, Brown JP, Burckhardt P, et al. Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med. 2002;346(9):653-661. 8. Body JJ, Gaich GA, Scheele WH, et al. A randomized double-blind trial to compare the efficacy of teriparatide [recombinant human parathyroid hormone (1-34)] with alendronate in postmenopausal women with osteoporosis. J Clin Endocrinol Metab. 2002;87(10):4528-4535. 9. American College of Obstetricians and Gynecologists (ACOG). Selective estrogen receptor modulators. ACOG Practice Bulletin: Clinical Management Guidelines for Obstetrician-Gynecologists: Number 39, October 2002. Obstet Gynecol. 2002;100(4):835-843. 10. No authors listed. Teriparatide (Forteo) for osteoporosis. Med Lett Drugs Ther. 2003;45(1149):9-10. 11. Marcus R, Wang O, Satterwhite J, Mitlak B. The skeletal response to teriparatide is largely independent of age, initial bone mineral density, and prevalent vertebral fractures in postmenopausal women with osteoporosis. J Bone Miner Res. 2003;18(1):18-23. 12. Rehman Q, Lang TF, Arnaud CD, et al. Daily treatment with parathyroid hormone is associated with an increase in vertebral cross-sectional area in postmenopausal women with glucocorticoid-induced osteoporosis. Osteoporos Int. 2003;14(1):77-81. 13. Orwoll ES, Scheele WH, Paul S, et al. The effect of teriparatide [human parathyroid hormone (1-34)] therapy on bone density in men with osteoporosis. J Bone Miner Res. 2003;18(1):9-17. AC-AEFOR082011 Page 12 of 17

14. No authors listed. Forteo approved for osteoporosis treatment. FDA Consum. 2003;37(2):4. 15. World Health Organization (WHO). Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: Report of a WHO study group. WHO Technical Report Series 843. Geneva, Switzerland: WHO; 1994. Available at: http://whqlibdoc.who.int/trs/who_trs_843.pdf. Accessed January 12, 2005. 16. Licata A. Osteoporosis in men: Suspect secondary disease first. Cleve Clin J Med. 2003;70(3):247-254. 17. Kim DH, Silber JS, Albert TJ. Osteoporotic vertebral compression fractures. Instr Course Lect. 2003;52:541-550. 18. Shulka VK. Treating osteoporosis with teriparatide: Many unknowns? Issues in Emerging Health Technologies. Issue 51. Ottawa, ON: Canadian Coordinating Office for Health Technology Assessment (CCOHTA); November 2003. 19. Canadian Coordinating Office for Health Technology Assessment (CCOHTA). Teriparatide for the treatment of osteoporosis. Emerging Drug List No 44. Ottawa, ON: CCOHTA; May 2003. 20. Deal C. The use of intermittent human parathyroid hormone as a treatment for osteoporosis. Curr Rheumatol Rep. 2004;6(1):49-58. 21. National Institute for Clinical Excellence (NICE). Technologies for the prevention and treatment of osteoporosis and prevention of osteoporotic fractures in postmenopausal women. Appraisal Consultation Document. London, UK: NICE; December 19, 2003. Available at: http://www.nice.org.uk/docref.asp?d=100352. Accessed January 12, 2004. 22. National Institute for Clinical Excellence (NICE). Bisphosphonates (alendronate, etidronate, risedronate), selective oestrogen receptor modulators (raloxifene) and parathyroid hormone (teriparatide) for the secondary prevention of osteoporotic fragility fractures in postmenopausal women. Technology Appraisal Guidance No 87. London, UK: NICE; January 2005. Available at: http://www.nice.org.uk/page.aspx?o=241341. Accessed September 27, 2006. 23. Eli Lilly and Company. Forteo teriparatide (rdna origin) injection. Prescribing Information. PA 9242 FSAMP. Indianapolis, IN: Eli Lilly; 2004. Available at: http://www.forteo.com. Accessed December 10, 2004. 24. Nevitt MC, Chen P, Dore RK, et al. Reduced risk of back pain following teriparatide treatment: A meta-analysis. Osteoporosis Int. 2006:17(2):273-280. 25. Stevenson M, Lloyd Jones M, De Nigris E, et al. A systematic review and economic evaluation of alendronate, etidronate, risedronate, raloxifene and teriparatide for the prevention and treatment of postmenopausal osteoporosis. Health Technol Assess. 2005;9(22):1-160. 26. Deal C, Omizo M, Schwartz EN, et al. Combination teriparatide and raloxifene therapy for postmenopausal osteoporosis: Results from a 6-month double-blind placebocontrolled trial. J Bone Miner Res. 2005;20(11):1905-1911. 27. Bilezikian JP, Rubin MR. Combination/sequential therapies for anabolic and antiresorptive skeletal agents for osteoporosis. Curr Osteoporos Rep. 2006;4(1):5-13. 28. Boucher M, Murphy G, Coyle D, et al. Bisphosphonates and teriparatide for the prevention of osteoporotic fractures in postmenopausal women. Technology Overview AC-AEFOR082011 Page 13 of 17

No. 22. Ottawa, ON: Canadian Agency for Drugs and Technologies in Health (CADTH); 2006. 29. Wells G A, Cranney A, Boucher M, et al. Bisphosphonates for the primary and secondary prevention of osteoporotic fractures in postmenopausal women: A meta-analysis. Technology Report Issue 69. Ottawa, ON: Canadian Agency for Drugs and Technologies in Health (CADTH); 2006. 30. Coyle D, Hadj Tahar A, Murphy G, et al. Teriparatide and bisphosphonates for treatment of osteoporosis in women: A clinical and economic analysis. Technology Report Issue 70. Ottawa, ON: Canadian Agency for Drugs and Technologies in Health (CADTH); 2006. 31. Bonnick SL. Osteoporosis in men and women. Clin Cornerstone. 2006;8(1):28-39. 32. Matsumoto T, Shiraki M, Hagino H, et al. Daily nasal spray of hpth(1-34) for 3 months increases bone mass in osteoporotic subjects: A pilot study. Osteoporos Int. 2006;17(10):1532-1538. 33. Angelopoulos NG, Goula A, Tolis G. Sporadic hypoparathyroidism treated with teriparatide: A case report and literature review. Exp Clin Endocrinol Diabetes. 2007;115(1):50-54. 34. Tuck SP, Datta HK. Osteoporosis in the aging male: Treatment options. Clin Interv Aging. 2007;2(4):521-536. 35. Saag KG, Shane E, Boonen S, et al. Teriparatide or alendronate in glucocorticoid-induced osteoporosis. N Engl J Med. 2007;357(20):2028-2039. 36. Rodríguez-Bores L, Barahona-Garrido J, Yamamoto-Furusho JK. Basic and clinical aspects of osteoporosis in inflammatory bowel disease. World J Gastroenterol. 2007;13(46):6156-6165. 37. Hodsman AB, Bauer DC, Dempster DW, et al. Parathyroid hormone and teriparatide for the treatment of osteoporosis: A review of the evidence and suggested guidelines for its use. Endocr Rev. 2005;26(5):688-703. 38. Silverman SL, Lane NE. Glucocorticoid-induced osteoporosis. Curr Osteoporos Rep. 2009;7(1):23-26. 39. Losada BR, Zanchetta JR, Zerbini C, et al. Active comparator trial of teriparatide vs alendronate for treating glucocorticoid-induced osteoporosis: Results from the Hispanic and non-hispanic cohorts. J Clin Densitom. 2009;12(1):63-70. 40. National Institute for Health and Clinical Excellence (NICE). Alendronate, etidronate, risedronate, raloxifene, strontium ranelate and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women (amended). NICE Technology Appraisal Guidance 161. London, UK: NICE; October 2008. 41. Saag KG, Zanchetta JR, Devogelaer JP, et al. Effects of teriparatide versus alendronate for treating glucocorticoid-induced osteoporosis: Thirty-six-month results of a randomized, double-blind, controlled trial. Arthritis Rheum. 2009;60(11):3346-3355. 42. Yamashita S. Bisphosphonates and other new therapeutic agents for the treatment of osteogenesis imperfecta. Clin Calcium. 2009;19(2):253-257. 43. National Prescribing Service Ltd. Teriparatide (Forteo) for severe osteoporosis. Pharmaceutical Benefits Scheme Listing. National Assessment of Drugs and Research (RADAR). Australia; NPS; August 2009. AC-AEFOR082011 Page 14 of 17

44. Canadian Expert Drug Advisory Committee (CEDAC). Teriparatide ACP submission (Forteo - Eli Lilly Canada Inc.). New indication: Glucocorticoid-induced osteoporosis. CEDAC Final Recommendation on Reconsideration and Reasons for Recommendation. Common Drug Review. Ottawa, ON: Canadian Agency for Drugs and Technologies in Health (CADTH); 2009. 45. Canadian Expert Drug Advisory Committee (CEDAC). Teriparatide ACP submission (Forteo - Eli Lilly Canada Inc.). Indication: Severe osteoporosis in women. CEDAC Final Recommendation. Common Drug Review. Ottawa, ON: Canadian Agency for Drugs and Technologies in Health (CADTH); 2010. 46. Bashutski JD, Eber RM, Kinney JS, et al. Teriparatide and osseous regeneration in the oral cavity. N Engl J Med. 2010;363(25):2396-2405. 47. Bukata SV, Puzas JE. Orthopedic uses of teriparatide. Curr Osteoporos Rep. 2010;8(1):28-33. 48. Aspenberg P, Genant HK, Johansson T, et al. Teriparatide for acceleration of fracture repair in humans: A prospective, randomized, double-blind study of 102 postmenopausal women with distal radial fractures. J Bone Miner Res. 2010;25(2):404-414. 49. Lyritis G, Marin F, Barker C, et al; EUROFORS Study Group. Back pain during different sequential treatment regimens of teriparatide: Results from EUROFORS. Curr Med Res Opin. 2010;26(8):1799-1807. 50. Schilcher J, Michaelsson K, Aspenberg P. Bisphosphonate use and atypical fractures of the femoral shaft. N Engl J Med. 2011;364(18):1728-1737. 51. National Institute for Health and Clinical Excellence (NICE). Alendronate, etidronate, risedronate, raloxifene, strontium ranelate and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women (amended). NICE Technology Appraisal Guidance 161 (Amended). London, UK: NICE; 2011. 52. Watts NB, Bilezikian JP, Camacho PM, et al; AACE Osteoporosis Task Force. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the diagnosis and treatment of postmenopausal osteoporosis. Endocr Pract. 2010;16 Suppl 3:1-37. 53. Takahata M, Awad HA, O'Keefe RJ, et al. Endogenous tissue engineering: PTH therapy for skeletal repair. Cell Tissue Res. 2012;347(3):545-552. 54. Borges JL, Freitas A, Bilezikian JP. Accelerated fracture healing with teriparatide. Arq Bras Endocrinol Metabol. 2013;57(2):153-156. 55. Zhang D, Potty A, Vyas P, Lane J. The role of recombinant PTH in human fracture healing: a systematic review. J Orthop Trauma. 2013 Feb 28. [Epub ahead of print] 56. Ohtori S, Inoue G, Orita S, et al. Comparison of teriparatide and bisphosphonate treatment to reduce pedicle screw loosening after lumbar spinal fusion surgery in postmenopausal women with osteoporosis from a bone quality perspective. Spine (Phila Pa 1976). 2013;38(8):E487-E492. 57. Berkoben M, Quarles LD. Hungry bone syndrome following parathyroidectomy. UpToDate Inc., Waltham, MA. Last reviewed May 2014. AC-AEFOR082011 Page 15 of 17

Appendix According to the FDA-approved labeling, teriparatide (Forteo) is contraindicated in any of the following individuals: Children and adolescents with open epiphyses; or Individuals who have been diagnosed with bone cancer or other cancers that have metastasized to the bones; or Individuals with hypercalcemia; or Individuals with Paget's disease of the bone; or Individuals with prior radiation therapy to the skeleton; or Women who are pregnant or nursing. Reviewed by a Board Certified Internist Reviewed by David Evans, MD, Medical Director, Active Health Management- Nov 2016 ACTIVEHEALTH MANAGEMENT. Footnotes [A] Note: For purposes of this guideline, independent risk factors for fracture include parental history of hip fracture, rheumatoid arthritis, alcohol use of 4 or more units per day, or current tobacco smoking. [ A in Context Link 1 ] [B] Note: A gender-specific database should be used for diagnosing osteoporosis. [ B in Context Link 1 ] [C] Failure is defined as documented continued bone loss after two or more years despite treatment with a bisphosphonate or SERM [ C in Context Link 1 ] [D] A gender-specific database should be used for diagnosing osteoporosis. [ D in Context Link 1 ] [E] For purposes of this policy, independent risk factors for fracture include parental history of hip fracture, rheumatoid arthritis, alcohol use of 4 or more units per day, or current tobacco smoking. [ E in Context Link 1 ] [F] For purposes of this policy, treatment failure is defined as documented continued bone loss after 2 or more years despite treatment with a bisphosphonate or SERM [ F in Context Link 1 ] AC-AEFOR082011 Page 16 of 17