1. Aetna considers daily injection of teriparatide (Forteo) medically necessary necessary for women with post-menopausal osteoporosis (bone mineral density [BMD] T score 2.5 or more standard deviations below the mean (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)**);  who are at high-risk for fractures (e.g., those who have had an osteoporotic fracture, or have certain risk factors for fracture***), and who have failed or are unable to tolerate either 2 oral bisphosphonates (e.g., alendronate [Fosamax], risedronate [Actonel]) or 1 oral bisphosphonate plus 1 selective estrogen receptor modulator (SERM) (e.g., raloxifene [Evista]), 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).

2. Aetna considers daily injection of teriparatide (Forteo) medically necessary for the treatment of men with primary or hypogonadal 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 of -1.0 or higher is considered normal)**;) who are at high-risk for fractures (e.g., those who have had an osteoporotic fracture, or have certain risk factors for fracture***), and who have failed* 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).

3. Aetna considers daily injection of teriparatide (Forteo) 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 of -1.0 or higher is considered normal)**), when both of the following criteria are met:

   1. 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); and 

   2. Members are at high-risk for fractures (e.g., those who have had an osteoporotic fracture, or have certain risk factors for fracture***), and have failed* 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).

4. Aetna considers teriparatide experimental and investigational for orthopedic uses (e.g., articular cartilage repair and fracture repair), osteogenesis imperfecta, osteoporosis associated with inflammatory bowel disease and for all other indications because its effectiveness for these indications has not been estanlished.

   * 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.

   ** A gender-specific database should be used for diagnosing osteoporosis.

   *** 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. 

   Notes:  Since the effects of long-term treatment with teriparatide are not known at this time, therapy for more than 2 years duration is considered experimental and investigational. 

   See also CPB 0134 - Bone Mass Measurements, CPB 0524 - Zoledronic Acid, and CPB 0562 - Biochemical Markers of Bone Remodeling.

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 post-menopausal 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 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” (SERMs) 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 gastro-intestinal 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, bone-forming 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 BMD.  Clinical studies showed that teriparatide lowered the risk of vertebral and non-vertebral fractures in post-menopausal 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 post-menopausal 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 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 1/3 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 3 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 teriparatide-treated 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, BMI, 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 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."

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 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 anti-resorptive 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 open-label uncontrolled study and a substantial proportion of patients did not complete the study on treatment.

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.

Combination therapy with teriparatide or parathyroid hormone (1-84) and an anti-resorptive 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 anti-resorptive 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 hPTH(1-34) spray for 3 months increased lumbar BMD (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 2 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 1 or more adverse event was not significantly different between 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), RANK-ligand, 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 long-term 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.

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.  Post-menopausal 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).  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.

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.