Aetna Teriparatide Form
This procedure is not covered
Background for this Policy
U.S. Food and Drug Administration (FDA)-Approved Indications
Teriparatide is available as Forteo (Eli Lilly and Company), Bonsity (Pfenex, Inc), and generic formulation (Alvogen, Inc).
Forteo (teriparatide) is a recombinant parathyroid hormone (PTH) product. It has an identical sequence to the 34 N‐terminal amino acids (the biologically active region) of the 84‐amino acid human PTH. Teriparatide and the active region of PTH bind to specific high‐affinity cell‐surface receptors with the same affinity.
Forteo (teriparatide) stimulates new bone formation on trabecular and cortical bone surfaces by preferential stimulation of osteoblastic activity over osteoclastic activity. It differs from PTH in that it is given subcutaneously once daily rather than being released endogenously. Teriparatide differs in chemical structure and pharmacological action from oral bisphosphonates, calcitonin, estrogen replacement therapy, and selective estrogen receptor modulators.
Forteo (teriparatide) is approved by the U.S. Food and Drug Administration (FDA) for the treatment of postmenopausal women with osteoporosis who are at high risk for fracture, to increase bone mass in men with primary or hypogonadal osteoporosis who are at high risk for fracture, and for treatment of men and women with glucocorticoid‐induced osteoporosis at high risk for fracture. High risk members include people who have had a history of osteoporotic fracture, multiple risk factors for fracture, or who have failed or are intolerant of previous osteoporosis therapy based on physician assessment.
Teriparatide is administered by once-daily subcutaneous injection in the thigh or abdomen. 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.
The most common adverse reactions (greater than 10%) to Forteo include arthralgia, pain, and nausea (Eli Lilly, 2021).
The labeling for teriparatide (Forteo) include warnings and precautions for osteosarcoma, hypercalcemia and cutaneous calcification, risk of urolithiasis, and orthostatic hypotension. An increase in the incidence of osteosarcoma was observed in male and female rats treated with teriparatide. Osteosarcoma has been reported in patients treated with Forteo in the post marketing setting; however, an increased risk of osteosarcoma has not been observed in observational studies in humans. Forteo has not been studied in patients with pre-existing hypercalcemia. Forteo may cause hypercalcemia and may exacerbate hypercalcemia in patients with pre-existing hypercalcemia. Serious reports of calciphylaxis and worsening of previously stable cutaneous calcification have been reported in the postmarketing setting in patients taking Forteo. In clinical trials, the frequency of urolithiasis was similar in patients treated with Forteo and patients treated with placebo. However, Forteo has not been studied in patients with active urolithiasis. Hypercalcemia may predispose patients to digitalis toxicity because Forteo transiently increases serum calcium (Eli Lilly, 2021).
Patients with bone metastases or a history of skeletal malignancies and metabolic bone diseases other than osteoporosis, should not be treated with Forteo. Forteo has not been studied in patients with pre-existing hypercalcemia. These patients should not be treated with Forteo because of the possibility of exacerbating hypercalcemia. Patients known to have an underlying hypercalcemic disorder, such as primary hyperparathyroidism, should not be treated with Forteo. In clinical trials, the frequency of urolithiasis was similar in patients treated with Forteo and placebo. However, Forteo has not been studied in patients with active urolithiasis. If active urolithiasis or pre-existing hypercalciuria are suspected, measurement of urinary calcium excretion should be considered. Forteo should be used with caution in patients with active or recent urolithiasis because of the potential to exacerbate this condition (Eli Lilly, 2021).
Use in specific populations (Eli Lilly, 2021):
In November 2020, the black box warning for osteosarcoma was removed for Forteo (Eli Lilly, 2021).
Per the labeling for Forteo, use of teriparatide for more than 2 years during a patient’s lifetime should only be considered if a patient remains at or has returned to having a high risk for fracture (Eli Lilly, 2021).
In October 2019, the U.S. FDA approved Bonsity (teriparatide injection; Pfenex) under the 505(b)(2) regulatory pathway, with Forteo (teriparatide injection; Eli Lilly) as the reference drug.
The efficacy of Bonsity was demonstrated by using the clinical studies for Forteo (teriparatide). Pfenex is conducting a comparative human factors study between Bonsity and Forteo.
Warnings and precautions of Bonsity include treatment duration beyond two years, bone metastases and skeletal malignancies, metabolic bone diseases, hypercalcemia and hypercalcemic disorders, urolithiasis or pre-existing hypercalciuria, orthostatic hypotension, and drug interactions. Bonsity carries a boxed warning for potential risk of osteosarcoma. The most common adverse reactions (greater than 10%) with Bonsity use were arthralgia, pain, and nausea (Optum, 2019; Pfenex, 2019).
Osteoporosis
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.
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: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.
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,
orwho have a contraindication to, or are intolerant of strontium ranelate,
and2) 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.
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.
Glucocorticoid-Induced Osteoporosis
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.
Osteoporosis Associated with Inflammatory Bowel Disease
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.
Osteoporosis in Patients with Duchenne Muscular Dystrophy
Nasomyont and colleagues (2020) stated that osteoporosis is a major concern in patients with Duchenne muscular dystrophy (DMD). In this novel study of teriparatide treatment in 6 patients with severe osteoporosis, bone health (fractures, vertebral morphometry, and DXA) remained stable, with no AEs. These findings would help inform future osteoporosis research in this challenging population. These investigators prospectively treated 6 patients with DMD who had severe osteoporosis with teriparatide 20 ug subcutaneously daily for 1 to 2 years. Inclusion criteria were long-term glucocorticoid therapy, and severe osteoporosis despite treatment with BP, or intolerance to BP. They examined long bone and vertebral fracture outcomes, including vertebral morphometry measures, BMD and bone mineral content (BMC), bone formation markers, safety indices, and AEs. The mean age at commencement of teriparatide was 17.9 years (range of 13.9 to 22.1 years). All 6 patients were on daily glucocorticoids (mean ± SD; duration 10.9 ± 2.5 years) and 5 were non-ambulatory; 5 patients had been treated with BP for 7.9 ± 4.2 years. All had vertebral and a history of long bone fragility fractures at baseline. Vertebral heights and Genant fracture grading remained stable. Long bone fracture rate appeared to decrease (from 0.84/year to 0.09/year); 1 patient sustained a long bone fracture at 6 months of treatment. Trajectories for change in BMD and BMC were not different post- versus pre-teriparatide. Procollagen type 1 amino-terminal propeptide (P1NP) increased, while laboratory safety indices remained stable and non-concerning; and no AEs were observed. The authors concluded that in 6 patients with DMD treated with teriparatide for severe osteoporosis, they observed stable bone health and modest increases in P1NP, without safety concerns. These researchers stated that further studies are needed to better understand teriparatide efficacy for treatment of osteoporosis in patients with DMD.
Atypical Femur Fractures
The American Society for Bone and Mineral Research Task Force’s 2nd report on “Atypical subtrochanteric and diaphyseal femoral fractures” (Shane et al, 2014) stated that “In the absence of a randomized, placebo‐controlled trial, no definite conclusion can be reached regarding the efficacy of TPTD [teriparatide] treatment of patients with AFF [atypical femur fractures]”.
Furthermore, an UpToDate review on “The use of bisphosphonates in postmenopausal women with osteoporosis” (Rosen, 2015) states that “Atypical femur fractures -- Another option in some cases would be the use of parathyroid hormone (PTH) in conjunction with comprehensive orthopedic intervention and surveillance. In some, but not all, case reports, teriparatide treatment improved fracture healing and pain in patients with atypical fractures. There are no randomized trials to definitively determine the efficacy of teriparatide in patients with atypical fractures. The results of randomized trials of teriparatide or PTH 1-84 in patients with distal radial or pelvic fractures (i.e., not atypical fractures) are conflicting, with one showing no benefit in fracture healing, and another showing benefit”.
Bone Marrow Edema
Galluccio and colleagues (2020) stated that bone marrow edema (BME) secondary to chronic regional pain syndrome (CRPS) after knee trauma is a disabling condition that presents with localized pain, allodynia, edema, decreased ROM and osteopenia. The management includes a variety of medications and rehabilitation. The treatment of refractory diseases is challenging for most physicians. These investigators presented 2 cases of refractory BME secondary to CRPS that were successfully treated with a short-term regimen of teriparatide. The rapid and sustained pain reduction with recovery of knee function for 2 years following administration of teriparatide demonstrated its potential for the treatment of BME due to CRPS.
The authors stated that 1 limitation of this case reports was that these researchers could not exclude the influence of previous therapy or a spontaneous resolution of the disease. However, the immediate improvement after starting teriparatide compared to the ineffectiveness of the previous drugs could be considered a direct effect. In refractory cases of BME secondary to CRPS, as well as for hip osteonecrosis, teriparatide might be considered as an alternative treatment, although further confirmation studies are needed.
Combined Extracorporeal Shock Wave and Teriparatide for Enhancement of Fragility Fractures Healing
Chen and colleagues (2021) noted that osteoporosis is a systemic bone disease characterized by decreased bone density and deterioration of bone microstructure, leading to an increased probability of fragility fractures. Once segmental bone defect occurs, it is easy to cause delayed union and nonunion. These researchers examined the efficacy of combined extracorporeal shock wave (ESW) and teriparatide-loaded hydrogel (T-Gel) on the cell activity and differentiation of osteoporosis derived bone marrow mesenchymal stem cells (OP-BMSCs) in-vitro and bone regeneration in osteoporotic segmental bone defects in-vivo. In-vitro, the strategy of combining ESW and T-Gel significantly enhanced OP-BMSCs proliferation, survival, migration, and osteogenic differentiation by up-regulating the alkaline phosphatase activity, mineralization, and expression of runt-related transcription factor-2, type I collagen, osteocalcin, and osteopontin. In the segmental bone defect models of osteoporotic rabbits, micro-CT evaluation and histological observation demonstrated this combined ESW and T-Gel injection significantly induced bone healing by enhancing the osteogenic activity of the local micro-environment in osteoporotic defects. The authors concluded that combined ESW-and T-Gel injection could regulate the poor osteogenic micro-environment in osteoporotic defects and showed potential for enhancing fragility fractures healing.
Distraction Osteogenesis
Umer et al (2014) examined the effect of teriparatide on new bone formation in a rat model of distraction osteogenesis. The experimental study comprised of male Sprague-Dawley rats (250 g each); they were allocated to 2 treatment groups:Femoral distraction was done for 3 weeks at the rate of 0.4 mm/day, followed by a further 4 weeks for consolidation. New bone formation was assessed using X-ray scoring system, bone densitometry and histology. The 12 rats in the study were divided into 2 groups of 6. All rats in the teriparatide group showed new bone formation whereas bone formation was present only in 2 (33.3 %) rats in the saline group. Bone densitometry showed that area (size) of the new bone formed adjacent to the margins of the osteotomy site as well as the total bone mineral content of the new bone was significantly higher (p < 0.05) in the teriparatide group. Histological analysis showed larger but statistically insignificant (p > 0.05) area of woven and trabecular new bone in the teriparatide group. The authors concluded that these findings suggested a promising role of parathyroid analog therapy in distraction osteogenesis for promoting bone formation and consolidation. This may have strong clinical implications in cases of limb lengthening and bone transport.
Fracture Healing / Fracture Union
In a systematic review and meta-analysis, Han and associates (2020) examined the role of teriparatide in improving hip fracture healing and function to provide a clinical guide. The systematic literature review identified RCTs and controlled studies evaluating teriparatide for elderly hip fractures; and a meta-analysis was performed using RevMan version 5.3. This study included 2 RCTs and 4 retrospective studies comprising 607 patients, with 269 and 338 patients in the teriparatide and control groups, respectively. The quality of these 6 studies was moderate. Compared to the control group, teriparatide reduced the time to union (weighted mean difference (WMD) = -1.95; 95 % CI: -3.23- to 0.68; p = 0.003) but did not improve the rate of fracture union at 3 months (OR = 1.46; 95 % CI: 0.50 to 4.24; p = 0.49) or 6 months (OR = 0.89; 95 % CI: 0.44 to 1.81; p = 0.75). In addition, teriparatide did not decrease the complications, need for re-operation, mortality, rate of deformity after fracture healing, and subsequent fracture or improve hip function. The authors concluded that the current limited evidence did not support that teriparatide improved fracture healing in hip fractures, due to study heterogeneity and various sources of biases. These researchers stated that further high-quality, large-sample trials are needed.
The authors stated that this review / meta-analysis had several drawbacks. First, this study included both RCTs and observational studies. One study reported that observational studies may exaggerate the actual efficacy of teriparatide. Second, slight clinical heterogeneity was observed due to differences in the daily or weekly doses of teriparatide and treatment periods between studies. The duration of treatment was too broad, from 6 weeks to 18 months. This could contribute to the heterogeneity. Third, in this meta-analysis, these investigators used meta-regression to detect the confounding factors, but it failed because the number of included studies was small; thus, they could not evaluate the possible confounding factors including reduction quality, BMD, osteoporosis, type of surgery, and type of fixation device. Therefore, the results should be interpreted with caution.
Yoon and Kim (2020) carried out an updated review of the evidence of TPD for fracture healing for the following 3 questions. First, does it decrease fracture healing time? Second, can it be an alternative treatment for nonunion? Third, does it aid in the union of atypical femoral fracture (AFF)? These investigators searched PubMed, Embase, and Cochrane Library including "Fracture" AND "nonunion" AND "Teriparatide. A total of 57 publications met inclusion criteria were summarized. This systemic review of the available literature revealed that TPD works positively with regard to enhancing fracture healing time and union of AFF. There were also many case studies on the use of TPD could be a potential new safe treatment for nonunion with no side effects. However, level 1 studies on the evidence of TPD are still lacking so far. The authors concluded that over the past 10 years, a growing body of evidence has accumulated suggesting that TPD could be an adjunct to enhance fracture healing or a therapeutic option to treat nonunion; however, greater evidence from large, prospective studies are needed. Moreover, these researchers stated that the European Calcified Tissue Society suggested the use of TPD following surgery of AFFs, even though strong evidence for improved fracture union is lacking. They stated that there is a need for RCTs to examine if TPD enhances the union of AFF may contribute to the risk of AFF.
Marongiu and colleagues (2020) noted that the healing of long bones diaphyseal fractures often can be impaired and resulted in delayed union and non-union. A number of therapeutic strategies have been proposed in combination with surgical treatment to enhance the healing process, such as scaffolds, growth factors, cell therapies and systemic pharmacological treatments. In a systematic review, these investigators examined available evidence of bone healing enhancement of acute long bone diaphyseal fractures. They carried out a systematic review by using PubMed/Medline; Embase and Ovid data-bases using the combination of the search terms "long-bones; diaphyseal fracture; bone healing; growth factors; cell therapies; scaffolds; graft; bone substitutes; orthobiologics; teriparatide". The initial search resulted in 4,156 articles of which 37 papers fulfilled the inclusion criteria and were the subject of this review. The studies included 1,350 patients (837 men and 513 women) with a mean age of 65.3 years old. The authors concluded that general lack of high-quality studies existed on the use of adjuvant strategies for bone healing enhancement in acute shaft fractures. Strong evidence supported the use of bone grafts, while only moderate evidence existed for demineralized bone matrix and synthetic ceramics. Conflicting results partially supported the use of growth factors and cell therapies in acute fractures. These researchers stated that teriparatide showed promising results, especially for AFFS and peri-prosthetic femoral fractures. Moreover, these investigators stated that further investigations and high-level studies are needed to examine the effectiveness of each of the different interventions and which combination would provide the best results in terms of bone healing rate, time to union and complications rate. Future efforts should be focused to reliably predict when a fracture is at high-risk for impaired bone healing and for selecting patients in whom the efficacy of therapeutic interventions to enhance fracture healing is assessed.
Canintika and Dilogo (2020) stated that fracture nonunion remains a great challenge for orthopedic surgeons. Approximately 5 to 10 % of bone fractures do not heal promptly, and require re-operations. Previously, several small studies have found that teriparatide has been found to induce union in those with delayed union and nonunion. However, to-date, no systematic reviews regarding the use of teriparatide for delayed union and nonunion are available. In a systematic review, these investigators examined the safety and efficacy of teriparatide in delayed union and nonunion. They carried out a literature search in PubMed, ScienceDirect, and Google Scholar until September 26, 2019. These researchers included studies involving adult patients (age of greater than 16 years) diagnosed with delayed union or nonunion fracture regardless of location (long bone, short bone, flat bone or irregular bone). The language was restricted to English and Indonesian. Outcomes that were recorded were fracture union and AEs. Initial search found 5,416 abstract and titles. Of these, 20 articles consisting of 64 subjects were retrieved. Of these, 15 case reports, 4 case series, and 1 prospective study were included. All of the studies administered subcutaneous injection of teriparatide 20 μg/day with mean duration of 7.3 ± 1.5 weeks to 9.7 months; 61 (95.3 %) of 64 subjects developed complete union. The follow-up ranged from 3 to 24 months. No side effects occurred during the follow-up period. The authors concluded that limited evidence demonstrated that daily subcutaneous injection of teriparatide 20 μg is a potential new safe treatment for delayed union and nonunion with no side effects. These researchers suggested the use of such drug, as it is safe and effective; however, further clinical studies are needed to examine its safety and efficacy.
In a systematic review and meta-analysis, Moon and colleagues (2020) evaluated RCTs that have reported the effects of teriparatide on bone-healing in osteoporotic hip and pelvic bone fractures to determine the efficacy of teriparatide in lowering the rate of treatment failure . A total of 2,809 studies were identified using a comprehensive literature search (Medline [n = 1,061], Embase [n = 1,395], and Cochrane Library n = 353]); 5 RCTs were included in the final analysis. Treatment failure rates at the last follow-up of osteoporotic hip and pelvic bone fractures between the teriparatide and control groups was the primary outcome. Treatment failure was defined as non-union, varus collapse of the proximal fragment, perforation of the lag screw, and any revision in cases due to mechanical failure of the implant during the follow-up period. The number of treatment failures in the teriparatide and placebo groups were 11.0 % (n = 20 out of 181) and 17.6 % (n = 36 out of 205), respectively. Although the rate of treatment failure in the teriparatide group was lower than that in the control group, this difference was not significant (OR, 0.81; 95 % CI: 0.42 to 1.53; p = 0.16; I2 = 42 %). The authors concluded that this meta-analysis did not identify any significant differences in the rate of treatment failure between the teriparatide and control groups at final follow-up. Based on these findings, these researchers believed that there is a lack of evidence to confirm the efficacy of teriparatide in reducing treatment failures in osteoporotic hip and pelvic bone fractures. They stated that further studies are needed to determine the efficacy of teriparatide on fracture healing and in improving other clinical outcomes.
The authors stated that this meta-analysis had several drawbacks. First, only 5 RCTs were included, which constituted a relatively small sample size. Second, although these investigators included RCTs involving osteoporotic hip and pelvic bone fractures, these studies also included various other fractures (e.g., femoral neck, inter-trochanteric, sub-trochanteric, pelvic bone), and their sub-classification could affect reported therapeutic outcomes. In particular, the study by Peichl et al (2011) exclusively included patients with pubic bone fractures; thus, making it difficult to conclude that the results of the present study were representativeness of osteoporotic pelvic bone fractures. However, there have been no RCTs to-date examining insufficiency fractures of the pelvic bone related to osteoporosis, and these researchers believed that osteoporotic pubic bone fracture is representative of insufficiency fractures of pelvic bone. In addition, various fracture-treatment protocols were identified including intra-medullary nailing, fixation using a dynamic hip screw or cannulated screw, and conservative treatment, and there could have been additional factors that might have affected treatment outcomes including treatment-related factors (e.g., surgical techniques, post-operative reduction), and patient-related factors (e.g., BMD, BMI, extent of pre-operative mobility, rehabilitation compliance). Third, each study had different treatment periods for teriparatide therapy and follow-ups. Although teriparatide is known to induce early callus formation after fractures, the long-term bone-healing effect can vary depending on the treatment period, as teriparatide can not only affect the early bone-formation phase, but also the remodeling phase. Furthermore, some studies have demonstrated that functional improvement depends on the period of teriparatide treatment; thus, it is important to consider studies with identical treatment periods when comparing clinical outcomes. Fourth, this study could not examine other key clinical outcomes. The 5 studies included in this meta-analysis evaluated varying clinical outcomes that were not consistent across studies (e.g., Harris hip score, Short-Form 12, Short-Form 36, Timed Up and Go (TUG) test, Johanson Hip Rating Questionnaire); thus, making it difficult to comprehensively evaluate the clinical effect of teriparatide. Mortality after fracture is an important clinical outcome in the elderly with hip and pelvic bone fractures, however, none of the studies included in this meta-analysis evaluated mortality after fractures. Furthermore, this study did not include any data comparing the safety of teriparatide versus placebo groups. As the number of complications reported in the enrolled studies was not adequate to conduct statistical analysis; and considering that the side effects related directly to teriparatide were low, it was difficult to include safety data on teriparatide. Fifth, the radiological outcomes of fracture healing evaluated in this study were limited. As the 5 studies selected for this meta-analysis included various radiological measurements at different time-points and stages of follow-up, it was difficult to conduct a meta-analysis for the fracture-healing effect of teriparatide in the early stages of bone healing, including those after a 6- or 12-week follow-up. This was a major drawback of this study given that teriparatide increases callus formation at an early stage of bone healing. In particular, as the acceleration of bone healing in the early stage of osteoporotic hip and pelvic bone fractures can improve rehabilitation and lower long-term mortality rates, simply because there is no significant difference in treatment outcomes at the last follow-up did not mean that there was no positive effect of teriparatide on osteoporotic hip and pelvic bone fractures; therefore, further studies on the bone-healing effect of teriparatide in the early stages of healing are needed.
Yoon and Kim (2020) carried out an updated review of the evidence of TPTD for fracture healing for the following questions. First, does it decrease fracture healing time? Second, can it be an alternative treatment for nonunion? Third, does it help the union of atypical femoral fracture (AFF)? These investigators searched PubMed, Embase, and Cochrane Library including "Fracture" AND "nonunion" AND "Teriparatide". A total of 57 publications meeting inclusion criteria were summarized. This systemic review of the available literature revealed that TPTD works positively with regard to enhancing fracture healing time and union of AFF. There are also many case studies on the use of TPTD could be a potential new safe treatment for nonunion with no side effects. However, level 1 studies on the evidence of TPTD are still lacking so far. Over the past 10 years, a growing body of evidence has accumulated suggesting that TPTD can be an adjunct to enhance fracture healing or a therapeutic option to treat nonunion; however, greater evidence from large, prospective trials are needed.
Rana and associates (2021) examined the influence of TPTD in surgically fixed osteoporotic intertrochanteric femur fractures and provided the groundwork for further research in this area. The results of osteoporotic patients who underwent only proximal femur nailing (PFN) for intertrochanteric femur fractures were prospectively compared to patients who received additional TPTD. These researchers identified the effect of TPTD on the time to fracture union, BMD, and other fracture related post-operative complications. The functional outcome was assessed using the lower extremity functional scale (LEFS). All patients were followed-up for 6 months by which time all the fractures united. However, in the TPTD group, time to fracture union was shortened by about 2 weeks and improvement in BMD and functional outcome were significantly better. The rate of migration of the helical, varus collapse, and femoral shortening did not show any relevant difference. The authors concluded that their preliminary attempt showed that early union coupled with better functional improvement and a substantial increase in BMD tips the balance in favor of TPTD in osteoporotic patients with intertrochanteric femur fractures. Moreover, these researchers stated that well-designed clinical trials with greater sample size are needed to substantiate these preliminary findings.
The authors stated that this study had several drawbacks. First, this was a preliminary attempt with small sample size and short follow-up, which made it difficult to make any definitive conclusion regarding secondary outcomes. Second, this study was not blinded due to ethical considerations. Although the criteria for outcome assessment were objective, some bias might still have come into play while recording the data. Third, these investigators did not compare the outcome of teriparatide with bisphosphonates, which are cheaper alternatives for osteoporosis management. Fourth, the radiology was carried out at 4 weekly intervals so the exact time of union could not be assessed precisely.
In a phase-II RCT, Nieves and colleagues (2022) examined if TPTD (20 μg/day) would results in improved radiologic healing, reduced pain, and improved functional outcome versus placebo over 3 months in pelvic fracture patients. This study enrolled 35 patients (women and men greater than 50 years old) within 4 weeks of pelvic fracture and examined the effect of blinded TPTD versus placebo over 3 months on fracture healing. Fracture healing from CT images at 0 and 3 months was evaluated as cortical bridging using a 5-point scale. The numeric rating scale (NRS) for pain was administered monthly. Physical performance was assessed monthly by Continuous Summary Physical Performance Score (CSPPS; based on 4-m walk speed, timed repeated chair stands, and balance) and the TUG test. The mean age was 82, and greater than 80 % were women. The intention-to-treat (ITT) analysis showed no group difference in cortical bridging score, and 50 % of fractures in TPTD-treated and 53 % of fractures in placebo-treated patients were healed at 3 months, unchanged after adjustment for age, sacral fracture, and fracture displacement. Median pain score dropped significantly in both groups with no group differences. Both CSPPS and TUG improved in the teriparatide group, whereas there was no improvement in the placebo group (group difference p < 0.03 for CSPPS at 2 and 3 months). The authors concluded that in this small randomized, blinded study, there was no improvement in radiographic healing (CT at 3 months) or pain with TPTD versus placebo; however, there was improved physical performance in TPTD-treated subjects that was not evident in the placebo group.
Fracture Repair
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.
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 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 (2014) performed a systematic literature review on the use of recombinant PTH in human fracture healing to: Requires Precertification:
Medicare Part B plans:
Precertification of teriparatide (Bonsity, Forteo) is required for participating providers and members in applicable Medicare Part B plan designs. For precertification of teriparatide, call (866) 503-0857, or fax (844) 268-7263.
Criteria for Initial Approval
Aetna considers teriparatide (Bonsity
,Forteo) medically necessary for the following indications:
Postmenopausal osteoporosis
When
anyof the following criteria are met:
Primary or hypogonadal osteoporosis in men
For male members with primary or hypogonadal osteoporosis when
anyof the following criteria are met:
Glucocorticoid-induced Osteoporosis
When
allof the following criteria are met:
Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).
Continuation of Therapy
Aetna considers continuation of teriparatide therapy medically necessary for all members (including new members) who are currently receiving the requested medication through a previously authorized pharmacy or medical benefit, who meet
oneof the following:
Other
The cumulative duration of parathyroid hormone analogs (e.g., teriparatide and abaloparatide) will not exceed a total of 24 months in the member’s lifetime unless the member remains at or has returned to having a high risk for fracture.
Related Policies
CPB 0134 - Bone Mass Measurements CPB 0524 - Zoledronic Acid CPB 0562 - Biochemical Markers of Bone Remodeling CPB 0804 - Denosumab (Prolia and Xgeva)Dosage and Administration
Teriparatide is available as Forteo and Bonsity.
Bonsity
Bonsity (teriparatide) for injection is available as 620 mcg/2.48 mL (250 mcg/mL) in single-patient-use pen containing 28 daily doses of 20 mcg.
Source: Pfenex, 2019
Forteo
Forteo (teriparatide) for injection is available as a multi-dose prefilled delivery device (pen) containing 28 daily doses of 20 mcg per dose for subcutaneous use.
Source: Eli Lilly, 2021
Experimental and Investigational
Aetna considers teriparatide experimental and investigational for the following (not an all-inclusive list) because its effectiveness for these indications has not been established: