Number: 0666

Table Of Contents

Applicable CPT / HCPCS / ICD-10 Codes


Note: 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.

  1. Criteria for Initial Approval

    Aetna considers teriparatide (Bonsity, Forteo) medically necessary for the following indications:

    1. Postmenopausal osteoporosis

      When any of the following criteria are met:

      1. Member has a history of fragility fractures; or
      2. Member has a pre-treatment T-score less than or equal to -2.5 or member has osteopenia (i.e., pre-treatment T-score greater than -2.5 and less than -1) with a high pre-treatment FRAX fracture probability (see Appendix C) and meets any of the following criteria:

        1. Member has indicators of very high fracture risk (e.g., advanced age, frailty, glucocorticoid use, very low T-scores [less than or equal to -3], or increased fall risk) ; or
        2. Member has failed prior treatment with or is intolerant to previous injectable osteoporosis therapy (e.g., zoledronic acid [Reclast], denosumab [Prolia], abaloparatide [Tymlos]); or
        3. Member has had an oral bisphosphonate trial of at least 1-year duration or there is a clinical reason to avoid treatment with an oral bisphosphonate (see Appendix A).
    2. Primary or hypogonadal osteoporosis in men

      For male members with primary or hypogonadal osteoporosis when any of the following criteria are met:

      1. Member has a history of an osteoporotic vertebral or hip fracture; or
      2. Member meets both of the following criteria:

        1. Member has a pre-treatment T-score less than or equal to -2.5 or member has osteopenia (i.e., pre-treatment T-score greater than -2.5 and less than -1) with a high pre-treatment FRAX fracture probability (see Appendix C); and
        2. Member has had an oral or injectable bisphosphonate trial of at least 1-year duration or there is a clinical reason to avoid treatment with a bisphosphonate (see Appendix A and Appendix B).
    3. Glucocorticoid-induced Osteoporosis

      When all of the following criteria are met:

      1. Member has had an oral or injectable bisphosphonate trial of at least 1-year duration or there is a clinical reason to avoid treatment with a bisphosphonate (see Appendix A and Appendix B); and
      2. Member is currently receiving or will be initiating glucocorticoid therapy at an equivalent prednisone dose of greater than or equal to 2.5 mg/day for 3 months or more; and
      3. Member meets any of the following criteria:

        1. Member has a history of a fragility fracture; or
        2. Member has a pre-treatment T-score of less than or equal to -2.5; or
        3. Member has osteopenia (i.e., pre-treatment T-score greater than -2.5 and less than -1) with a high pre-treatment FRAX fracture probability (see Appendix C).

    Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

  2. 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 one of the following: 

    1. Member has received less than 24 months of therapy and has not experienced clinically significant adverse events during therapy; or
    2. Member has received 24 months of therapy or more and meets both of the following:

      1. Member has experienced clinical benefit (i.e., improvement or stabilization in T-score since the previous bone mass measurement); and
      2. Member has not experienced any adverse effects.
  3. 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.

  4. Related Policies

    1. CPB 0134 - Bone Mass Measurements
    2. CPB 0524 - Zoledronic Acid
    3. CPB 0562 - Biochemical Markers of Bone Remodeling
    4. CPB 0804 - Denosumab (Prolia and Xgeva)

Dosage and Administration

Teriparatide is available as Forteo and 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.

  • The recommended dose is 20 mcg subcutaneously once a day for all FDA-approved indications (treatment of postmenopausal women with osteoporosis at high risk for fracture, increase of bone mass in men with primary or hypogonadal osteoporosis at high risk for fracture, and treatment of men and women with glucocorticoid-induced osteoporosis at high risk for fracture).
  • Use of the drug for more than 2 years during a person’s lifetime is not recommended.

Source: Pfenex, 2019


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.

  • The recommended dose is 20 mcg subcutaneously once a day for all FDA-approved indications (i.e., treatment of postmenopausal women with osteoporosis at high risk for fracture or persons who have failed or are intolerant to other available osteoporosis therapy, increase of bone mass in men with primary or hypogonadal osteoporosis at high risk for fracture or persons who have failed or are intolerant to other available osteoporosis therapy, and treatment of men and women with osteoporosis associated with sustained systemic glucocorticoid therapy at high risk for fracture or persons who have failed or are intolerant to other available osteoporosis therapy).
  • Use of Forteo for more than 2 years during a person’s lifetime should only be considered if individual remains at or has returned to having a high risk for fracture.

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:

  • Bone marrow edema
  • Combined extracorporeal shock wave and teriparatide for enhancement of fragility fractures healing
  • Cranio-facial ciliopathies
  • Hypoparathyroidism
  • Hungry bone syndrome
  • Joint erosions in rheumatoid arthritis
  • Orthopedic uses (e.g., articular cartilage repair, atypical femur fractures, fracture repair, nonunion fractures, and osteonecrosis of the jaw)
  • Osteogenesis imperfecta
  • Osteoporosis associated with inflammatory bowel disease
  • Osteoporosis from Duchenne muscular dystrophy
  • Promotion of bone formation and consolidation in distraction osteogenesis
  • Post spinal cord injury osteoporosis
  • Prosthesis fixation following total knee replacement
  • Spinal fusion (including reducing pedicle screw loosening following spinal fusion)
  • Stress fracture treatment.


CPT Codes / HCPCS Codes / ICD-10 Codes

Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

Other CPT codes related to the CPB:

20100 - 29999 Musculoskeletal system [e.g. articular cartilage repair and fracture repair]
76977 Ultrasound bone density measurement and interpretation, peripheral sites(s), any method
77078 - 77081 Computed tomography, bone mineral density study, one or more sites; axial skeleton (e.g., hips, pelvis, spine), appendicular skeleton (peripheral) (e.g., radius, wrist, heel) or dual energy x-ray absorptiometry (DXA), bone density study, one or more sites: axial skeleton (e.g., hips, pelvis, spine), appendicular skeleton, (peripheral) (eg, radius, wrist, heel), or vertebral fracture assessment

CPT codes not covered for indications listed in the CPB:

0101T Extracorporeal shock wave involving musculoskeletal system, not otherwise specified

HCPCS codes covered if selection criteria are met:

J3110 Injection, Teriparatide, 10 mcg

Other HCPCS codes related to the CPB:

E0747 Osteogenesis stimulator, electrical, noninvasive, other than spinal applications
E0760 Osteogenesis stimulator, low intensity ultrasound, noninvasive
J1740 Injection, ibandronate sodium, 1 mg
J3489 Injection, zoledronic acid, 1mg

ICD-10 codes covered if selection criteria are met:

M80.00x+ - M81.6 Osteoporosis
M81.8 Other osteoporosis without current pathological fracture [not covered for drug-induced osteoporosis and osteoporosis associated with inflammatory bowel disease]

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

E20.0 - E20.9 Hypoparathyroidism
E83.81 Hungry bone syndrome
G71.01 Duchenne or Becker muscular dystrophy
M05.0 - M05.09, M05.20 - M06.39, M06.80 - M06.9 Rheumatoid arthritis [joint erosions]
M43.20 - M43.28 Fusion of spine
M84.30xx+ - M84.38xx+ Stress fractures
M87.08 Idiopathic aseptic necrosis of bone, other site [jaw]
Numerous options Nonunion of fracture [7th character "K"]
Q18.8 - Q18.9 Other specified congenital malformations of face and neck [cranio-facial ciliopathies]
Q67.4 Other congenital deformities of skull, face and jaw [cranio-facial ciliopathies]
Q75.0 – Q75.9 Other congenital malformations of skull and face bones [cranio-facial ciliopathies]
Q78.0 Osteogenesis imperfecta
R60.9 Edema, unspecified [bone marrow edema]
S72.001+ - S72.92x+ Fracture of femur [for the treatment of atypical femur fractures]
T84.030+ - T84.039+ Mechanical loosening of internal prosthetic joint [reducing pedicle screw loosening following spinal fusion]


U.S. Food and Drug Administration (FDA)-Approved Indications

  • Treatment of postmenopausal women with osteoporosis at high risk for fracture (defined herein as having a history of osteoporotic fracture or multiple risk factors for fracture) or who have failed or are intolerant to other available osteoporosis therapy.
  • Increase of bone mass in men with primary or hypogonadal osteoporosis at high risk for fracture or who have failed or are intolerant to other available osteoporosis therapy.
  • Treatment of men and women with glucocorticoid-induced osteoporosis at high risk for fracture (daily dosage equivalent to 5 mg or greater of prednisone) at high risk for fracture or who have failed or are intolerant to other available osteoporosis therapy.

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):

  • Pregnancy: Consider discontinuing when pregnancy is recognized
  • Lactation: Breastfeeding is not recommended
  • Pediatric Use: Forteo should not be used in pediatric and young adult patients with open epiphyses due to increased baseline risk of osteosarcoma.

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).


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:
  1. daily injections of placebo,
  2. teriparatide 20 mcg, or
  3. 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.

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, 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.

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:
  1. teriparatide and
  2. saline, both given subcutaneously for 7 weeks.

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
  1. evaluate the evidence for recombinant PTH in human fracture healing, and
  2. 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.

In a meta-analysis, Shi and associates (2016) evaluated the effectiveness of teriparatide for fracture healing.  These investigators searched PubMed, the Cochrane Library, and Embase in August 2016 for RCTs that concerned the treatment of teriparatide for fracture healing.  This meta-analysis included 5 trials with a total of 380 patients.  There was a significant effectiveness with regards to function improvement in patients following fracture, however, there was no significant effectiveness with regards to time of radiographic fracture healing, fracture healing rate and reduction in pain.  The authors concluded that the findings of this analysis showed that administration of teriparatide following fracture lacked the effectiveness for fracture healing.  Moreover, teriparatide administration had no apparent adverse effects.  They stated that these results should be interpreted with caution because of some r limitations.  They stated that more high-quality RCTs are needed to confirm whether teriparatide improves fracture healing.

Kim and colleagues (2017) evaluated the evidence of teriparatide for fracture healing and functional recovery in osteoporotic patients.  They performed a literature search in PubMed, Embase, Web of Science, and the Cochrane Library using terms including "Fracture" [tiab] AND "Teriparatide [tiab] OR "PTH" [tiab].  This systematic review included 6 randomized clinical trials, 4 well-controlled retrospective studies, and 1 retrospective post-hoc subgroup analysis.  Fracture location was 2 in pelvis, 3 in proximal femur, 1 in distal femur, 1 in shoulder, 2 in wrist and 2 in spine.  The use of teriparatide yielded positive effects on radiographic bone healing in 6 studies, but was not associated with better radiographic outcome in 3.  In terms of functional recovery, teriparatide injection was related with decrease in pain or shorter time to mobilization in 6 studies, but not related with pain numerical scale and mobility in 3.  The authors concluded that these findings suggested that teriparatide provided selective advantages to fracture healing or functional recovery in the management of osteoporotic fractures.  Moreover, they stated that a better understanding of the role of teriparatide on osteoporotic fractures requires greater evidences from large volume prospective trials.

Fragility Fractures in Diabetics

Gonnelli et al (2015) stated that patients with diabetes mellitus (DM) are at greater risk of fractures mostly due to not only extra-skeletal factors, such as propensity to falls, but also to bone quality alteration, which reduces bone strength. In patients with DM, insulin deficit and hyperglycemia seem to play a role in determining bone formation alteration by advanced glycation end-product (AGE) accumulation which directly influences osteoblast activity. Although there are conflicting data in the literature, adequate glycemic control with hypoglycemic treatment may be an important element in preventing bone tissue alterations in both type 1 and type 2 DM. Diabetes status is a predictive of future hip and major osteoporosis fractures independently of BMD and the Fracture Risk Assessment Tool (FRAX) probability (FRAX computes the 10-year probability of hip fracture or a major osteoporotic fracture [clinical spine, hip, forearm or humerus]). Attention should be paid to the use of thiazolidinediones, especially in older women, because the direct negative effect on bone could exceed the positive effect of glycemic control. Systematic screening for complications and fall prevention efforts, along with calcium and vitamin D repletion and adequate physical activity, represents the mainstay of fracture prevention in DM patients. All anti-catabolic drugs (raloxifene, BP, denosumab) seem to be effective in DM patients. On the basis of pathophysiological evidence that suggested low bone formation in DM patients, osteo-anabolic therapies such as teriparatide might represent an important therapeutic option for DM patients with severe osteoporosis and/or multiple fractures. The search for better methods for the identification of fragility fracture risk in the growing population of adult and elderly subjects with DM might be considered a clinical priority which could improve the prevention of fracture in DM patients.

An UpToDate review on “Bone disease in diabetes mellitus” (Hordon, 2015) does not mention teriparatide as a therapeutic option.

Hungry Bone Syndrome

An UpToDate review on “Hungry bone syndrome following parathyroidectomy” (Berkoben and Quarles, 2014) does not mention the use of teriparatide as a therapeutic option.


In a prospective, open-label study, Upreti and colleagues (2017) evaluated the effectiveness of teriparatide in the treatment of patients with hypoparathyroidism.  All patients with hypoparathyroidism presented to the endocrinology out-patient department were included and were exhibited injection teriparatide 20 μg twice-daily that was gradually reduced to 10 μg twice-daily along with calcium, active vitamin D (alfacalcidol), and hydrochlorothiazide.  Oral calcium and alfacalcidol doses were also reduced to maintain serum calcium within normal range.  The quality of life (QOL) score was calculated using RAND 36 QOL questionnaire at baseline and termination of the study.  Paired t-test was used to calculate pre- and post-treatment variables.  A total of 8 patients (2 males) were included in this study with mean age of 35.8 years.  Teriparatide treatment led to the improvement in serum calcium (6.81 to 8.84 mg/dL), phosphorous (5.8 to 4.2 mg/dL), and 24-h urinary calcium excretion (416 to 203.6 mg).  Parameters of QOL showed the improvement in overall QOL, physical performance, energy, and fatigue scores.  No major adverse events (AEs) were noted.  The authors concluded that treatment of hypoparathyroidism with teriparatide resulted in improvement in calcium profile, reduction in hypercalciuria, and improvement in QOL, and treatment was well-tolerated.  Moreover, they stated that further larger studies are needed to establish the clinical value of teriparatide in the treatment of hypoparathyroidism.  The main drawback of this study were its small sample size (n = 8) and non-evaluation of bone turnover markers.

Joint Erosions in Rheumatoid Arthritis

In a RCT, Solomon and colleagues (2017) evaluated the effects of teriparatide on joint erosion volume in rheumatoid arthritis (RA) patients treated with a tumor necrosis factor inhibitor (TNFi).  Participants included 24 patients with erosive RA, osteopenia, and disease activity controlled on a TNFi for at least 3 months; 50 % were randomized to receive teriparatide for 1 year and the others constituted a wait-list control arm.  Subjects and primary rheumatologists were not masked to treatment assignment, but assessment of all outcomes was blinded.  The primary outcome was change in erosion volume measured by computed tomography at 6 anatomic sites.  Significance within each hand and anatomic site was based on a 2-tailed test, with p-value < 0.05 considered statistically significant.  Baseline characteristics of the treatment arms were well balanced.  After 52 weeks, median (interquartile) erosion volume change in the teriparatide group was -0.4 mm3 (-34.5 to 29.6) and did not differ significantly from that in controls of 9.1 mm3 (-29.6 to 26.4) (p = 0.28).  No significant change in erosion volume was noted at the radius, ulna, or metacarpophalangeal joints; BMD improved at the femoral neck and lumbar spine in the teriparatide group.  The authors concluded that teriparatide treatment for 1 year did not significantly reduce erosion volume in the hands or wrists of patients with established RA, controlled on TNFi treatment.

Loosening of Pedicle Screws

Ohtori and colleagues (2013) stated that failure of fixation caused by loosening of 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:
  1. a teriparatide group (daily subcutaneous injection of 20 μg of teriparatide, n = 20),
  2. a bisphosphonate group (daily oral administration 2.5 mg of risedronate, n = 20), and
  3. 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 teriparatide increased the quality of the lumbar spine bone marrow and pedicle cortex.  These preliminary findings need to be validated by well-designed studies.

Nonunion Fractures

In a case-series study, Mancilla et al (2015) examined the effect of teriparatide on the healing of long bone nonunion fractures. These investigators performed a retrospective chart review of patients with fracture nonunion, aged 10 to 99 years who were treated with teriparatide. The primary end-points were radiographic evidence of callus formation and fracture union, ability to bear weight without affected limb limp, and normal range of motion (ROM) and strength. A total of 6 patients aged 19 to 64 years with tibial or femoral fractures that had not healed for 3 to 36 months were treated with teriparatide 20 μg/day. Accelerated healing of fracture nonunion was confirmed in 5 of 6 patients with time to complete union of 3 to 9 months. The shortest time to recovery was observed in younger patients without co-morbidities. Treatment was well-tolerated. The authors concluded that teriparatide is a promising treatment for nonunion fractures, but its response depends on associated co-morbidities. They stated that the potential benefit of teriparatide as an adjunct to treat nonunion justifies RCTs to determine its safety and effectiveness in broader populations.

Treatment of Basicervical Peri-Trochanteric Fracture Nonunion

Ho et al (2022) stated that the nonunion rate of surgically treated basicervical peri-trochanteric fractures has been reported to be as high as 9 %.  Due to the high 1-year mortality rate following revision surgery, finding an effective non-surgical therapeutic option is of interest.  Over the past 10 years, numerous reports have been published that have suggested teriparatide as an effective treatment for certain types of fracture nonunion.  However, the literature focused on teriparatide treatment for proximal femoral fracture nonunion is scanty.  These investigators presented the case of a 70-year-old man who suffered from a left hip basicervical peri-trochanteric fracture; and received cephalon-medullary nail fixation.  Nine months following the surgery, the patient still complained of left hip pain referring to the medial thigh with an antalgic limping gait.  No sign of healing was noted for more than a consecutive 3 months of follow-up.  Fracture nonunion was diagnosed and further confirmed by CT scan.  The patient preferred non-surgical treatment after thorough discussion.  He then received 4 months of subcutaneous teriparatide injections, 20 ug daily.  After less than 4 months of teriparatide treatment, a follow-up CT confirmed fracture union and the patient's pain subsided.  The patient also tolerated independent ambulation afterward.  The authors concluded that teriparatide has been reported to be an effective treatment for certain types of fracture nonunion.  This case went a step further to expand its possible application for basicervical peri-trochanteric fracture nonunion.  Moreover, these researchers stated that further, large- scale studies are needed to confirm these findings, and to build up a therapeutic protocol.

Osteogenesis Imperfecta

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.

Osteonecrosis of the Jaw

Kim and colleagues (2014) noted that the administration of teriparatide in conjunction with periodontal care could provide faster and more favorable clinical outcomes in previously refractory bisphosphonate (BP)-related osteonecrosis of the jaws (BRONJ) cases compared to conventional dental care, combination of surgery and anti-microbial treatment. These investigators also found that underlying vitamin D levels might influence the response to teriparatide treatment. A total of 24 cases of intractable BRONJ were included: 15 subjects were assigned to the teriparatide group and the other 9 subjects, who refused teriparatide administration, were assigned to the non-teriparatide group. All subjects in both groups continued calcium and vitamin D supplementation and the teriparatide group additionally received a daily subcutaneous injection of 20 μg teriparatide for 6 months. While 60.0 % of the non- teriparatide group showed 1 stage of improvement in BRONJ, 40.0 % of the group did not show any improvement in disease status. In the teriparatide group, 62.5 % of the treated subjects showed 1 stage of improvement and the other 37.5 % demonstrated a marked improvement, including 2 stages of improvement or complete healing, and there was not a single case that did not improve. The clinical improvement of BRONJ was statistically better in the teriparatide group after the 6-month treatment (p < 0.05). Moreover, patients with higher baseline serum 25(OH)D levels showed better clinical therapeutic outcomes with teriparatide. The authors observed the beneficial effects of teriparatide on BRONJ, and subjects with optimal serum vitamin D concentrations seemed to reap the maximum therapeutic effects of TPTD. They stated that a prospective RCT is needed to further evaluate the therapeutic efficacy of teriparatide in the resolution of BRONJ.

Khan et al (2015) provided a systematic review of the literature from January 2003 to April 2014 pertaining to the incidence, pathophysiology, diagnosis, and treatment of osteonecrosis of the jaw (ONJ), and offered recommendations for its management based on multi-disciplinary international consensus. Osteonecrosis of the jaw is associated with oncology-dose parenteral anti-resorptive therapy of BP and denosumab (Dmab). The incidence of ONJ is greatest in the oncology patient population (1 % to 15 %), where high doses of these medications are used at frequent intervals. In the osteoporosis patient population, the incidence of ONJ is estimated at 0.001 % to 0.01 %, marginally higher than the incidence in the general population (less than 0.001 %). New insights into the pathophysiology of ONJ include anti-resorptive effects of BPs and Dmab, effects of BPs on gamma delta T-cells and on monocyte and macrophage function, as well as the role of local bacterial infection, inflammation, and necrosis. Advances in imaging include the use of cone beam computerized tomography assessing cortical and cancellous architecture with lower radiation exposure, magnetic resonance imaging, bone scanning, and positron emission tomography, although plain films often suffice. Other risk factors for ONJ include glucocorticoid use, maxillary or mandibular bone surgery, poor oral hygiene, chronic inflammation, diabetes mellitus, ill-fitting dentures, as well as other drugs, including anti-angiogenic agents. Prevention strategies for ONJ include elimination or stabilization of oral disease prior to initiation of anti-resorptive agents, as well as maintenance of good oral hygiene. In those patients at high risk for the development of ONJ, including cancer patients receiving high-dose BP or Dmab therapy, consideration should be given to withholding anti-resorptive therapy following extensive oral surgery until the surgical site heals with mature mucosal coverage. Management of ONJ is based on the stage of the disease, size of the lesions, and the presence of contributing drug therapy and co-morbidity. Conservative therapy includes topical antibiotic oral rinses and systemic antibiotic therapy. Localized surgical debridement is indicated in advanced non-responsive disease and has been successful. The authors noted that early data have suggested enhanced osseous wound healing with teriparatide in those without contraindications for its use. Experimental therapy includes bone marrow stem cell intralesional transplantation, low-level laser therapy, local platelet-derived growth factor application, hyperbaric oxygen, and tissue grafting.

An UpToDate review on “Medication-related osteonecrosis of the jaw in patients with cancer” (Berenson and Stopeck, 2015) states that “Other nonsurgical treatment strategies -- Limited data suggest potential benefit for a variety of other nonsurgical treatment strategies including pentoxifylline and vitamin E, low-level laser irradiation, hyperbaric oxygen, parathyroid hormone, and topical application of medical ozone, although none can be considered a standard approach at this time”.

Anabtawi and colleagues (2021) stated that medication-related osteonecrosis of the jaw (MRONJ) is a complex disease that can be associated with multiple morbidities and is challenging to treat.  These researchers examined the literature on the role and efficacy of teriparatide (TPTD) as a treatment for MRONJ.  The clinical, radiological, histopathological and serological parameters used to evaluate therapeutic response have been described.  Electronic databases were searched to retrieve articles (April 2005 to April 2020) based on strict inclusion criteria.  A total of 17 articles were included in this review.  Of the 91 patients treated; only 6 received TPTD as a stand-alone treatment.  There were significant variations in defining therapeutic outcomes and measuring therapeutic response.  The longest follow-up period was 26 months, and 12 studies failed to report follow-up.  The overall quality of evidence was weak with potential for a high risk of bias, making it difficult to determine the efficacy of TPTD and its long-term effects.  However, TPTD may play a role in the treatment of intractable MRONJ in osteoporotic patients or those unfit for surgery.  The authors concluded that randomized clinical trials on larger patient cohorts with long-term follow-up is needed to confirm the safety and effectiveness of TPTD in the treatment of MRONJ.

Dos Santos Ferreira et al (2021) noted that considering the lack of studies determining the real effectiveness of TPTD therapy in individuals who develop MRONJ, these investigators combined the data published on the effect of TPTD on cases of MRONJ into a comprehensive analysis of clinical features.  They carried out an electronic search in 6 databases.  Descriptive analyses of clinicodemographic data of MRONJ were performed.  Poisson regression was also done to examine predictors of total resolution of MRONJ treated with TPTD.  A total of 26 publications comprising 111 cases were included.  Most reported cases affected women (82.0 %) with a mean age of 76.54 years.  Osteoporosis (76.5 %) represented the main reason for using anti-resorptive drugs, with bisphosphonates (98.1 %) as the most frequently reported.  Co-morbidities were commonly present.  The most related trigger factor of MRONJ was dental extraction (61.7 %).  Mandible (75.8 %) was the most commonly affected site, with a mean evolution time of 5 months; MRONJ stage 2 (61.3 %) was the most prevalent.  Regarding TPTD treatment, in 45.1 % cases, TPTD was used alone, with the total resolution being observed in 59.5 % of the individuals.  Associated therapy (54.9 %) included surgery, antibiotic therapy, and laser therapy; mean follow-up was 8.7 months.  Poisson regression demonstrated that individuals with MRONJ stage 1 were 1.21 times more likely to present total resolution of osteonecrosis than individuals with MRONJ stage 3 (CI: 1.02 to 1.43; p < 0.023).  Individuals who had undergone treatment with TPTD in association with another therapeutic modality were 1.21 times more likely to present total resolution of osteonecrosis than those who had undergone treatment with TPTD alone (CI: 1.40 to 1.39; p < 0.010).  The authors concluded that TPTD in combination with another therapy, especially antibiotic therapy, should be considered an effective therapeutic modality for MRONJ.  Moreover, these researchers stated that although the results were promising, the evidence on this issue, for the most part, was based on the results of case series and case reports, which downgraded the level of confidence in the estimates.  They stated that higher quality evidence is needed to support the findings of this systematic review and to aid stakeholders in the development of a more consistent and evidence-based management approach to this complication. 

The authors stated that this systematic review had several drawbacks.  First, case reports, case series, or retrospective studies were the sources of information on the effectiveness of TPTD for the treatment of MRONJ.  There was only 1 randomized study examining the use of TPTD for MRONJ management, and no standalone treatment or as part of a multi-therapy regimen.  Moreover, available data from some studies, especially those including case series, were pooled and described by means of descriptive statistics.  Some information, such as data on co-morbidities and duration of TPTD use, were missing, precluding a more powerful statistical analysis.  Second, few studies considered serological parameters such as the markers of bone resorption serum N- or C-terminal telopeptide (sCTX) to examine the patient response to therapy with TPTD.  Third, no study examined the role of patient genetic susceptibility to MRONJ and to response to treatment.  Assessments of polymorphisms in the cytochrome P450 gene, CYP2C8 gene, or farnesyl pyrophosphate synthase gene and evaluations of the influence of ethnic characteristics would be useful for the assessment of the risk of developing MRONJ.  With the increasing aging of the population, oral and maxillofacial surgeons can observe a greater proportion of patients exposed to anti-resorptive drugs, especially BPs.  Although many studies reported recommendations regarding diagnosis, knowledge of therapy and prophylaxis for MRONJ and the understanding of non-invasive therapeutic options are still a challenge.  In this respect, based on the global results of this study, TPTD therapy in association with another therapeutic modality may be considered to be effective management for MRONJ.  Moreover, because of the anabolic action of TPTD, information about the benefits of treatment in situations that need enhancement of bone remodeling is misleading.

Post Spinal Cord Injury Osteoporosis

In a pilot study, Gordon et al (2013) evaluated the response of bone to 2 anabolic stimuli, teriparatide and mechanical loading, in subjects with spinal cord injury (SCI).  This study consisted of 12 non-ambulatory chronic SCI  subjects.  The subjects were administered open-label teriparatide 20 μg/day while undergoing robotic-assisted stepping 3 times a week for 6 months, followed by 6 months of teriparatide alone.  Bone status was evaluated at 3, 6, and 12 months by using dual-energy x-ray absorptiometry to calculate bone mineral density (BMD) at the spine and hip, magnetic resonance imaging to assess bone microarchitecture of the distal tibia, and serum bone markers.  Mean (SD) baseline BMD measurements at the spine and the left and right total hip were 1.05 ± 0.162 g/cm(2), 0.638 ± 0.090 g/cm(2) and 0.626 ± 0.088 g/cm(2), respectively.  After 6 months of treatment, BMD changed 2.19 % ± 3.61 %, 0.02 % ± 2.21 %, and 0.74 % ± 2.80 % at the spine, and left and right total hip, respectively.  These changes were not statistically significant (p > 0.05 for all).  Magnetic resonance imaging supported an anabolic effect after 3 months of treatment with significant (p < 0.05) changes in trabecular thickness, 4.4 % ± 4.06 %; surface-to-curve ratio, 23.6 % ± 22.3 %; and erosion index, -17.04 % ± 12.9 %.  Although the trend remained after 6 months, statistical significance was not retained.  At 6 months, bone markers indicated an increase in mean levels of bone-specific alkaline phosphatase, 53.8 % ± 62.9 %; C-terminal telopeptides of type I collagen, 137.6 % ± 194.6 %; and intact amino-terminal propeptide of type I procollagen, 61.4 % ± 99.3 %.  The authors concluded that in this limited pilot study, teriparatide and mechanical loading resulted in a numerical but not statistically significant increase in lumbar spine BMD and no significant BMD changes at the hip.  Magnetic resonance imaging at the distal tibia suggested an anabolic effect, but the high sensitivity offered by this technique was challenged by the limited ability to obtain analyzable data from all the subjects.  They stated that further studies that involve longer treatment periods and greater mechanical loading are needed.

Furthermore, an UpToDate review on “Chronic complications of spinal cord injury” (Abrams and Wakasa, 2018) states that “Osteoporosis affects bones below the level of the SCI and increases the risk of fracture.  The role of bisphosphonates in this setting is under investigation”. 

Prevention of Site-Specific Non-Vertebral Fractures at the Wrist and Hip

In a systematic review, Chen and colleagues (2019) updated the treatment with teriparatide for fracture prevention.  Electronic databases, including OVID Medline, OVID Embase, and the Cochrane Library, were searched on February 9, 2018, to identify published systematic reviews and meta-analyses addressing treatment with teriparatide for fracture prevention, and A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2) was used to assess the quality of included studies.  A total of 17 studies were included; 3 were rated as high quality, 3 were rated as moderate quality, 6 were rated as low quality, and 5 were rated as critically low quality.  Teriparatide reduced vertebral and overall non-vertebral fractures in osteoporotic patients regardless of the existence of precipitating conditions, including post-menopausal status, glucocorticoid treatment, and chronic kidney disease, as compared with placebo, but not the site-specific non-vertebral fractures of the wrist and hip.  Teriparatide did not more effectively reduce fracture risks when compared with other medications, such as bisphosphonates, SERMs, RANKL (receptor activator of nuclear factor kappa-beta ligand) inhibitor, or strontium ranelate.  The authors concluded that teriparatide was safe and was not associated with an increased rate of AEs when compared with other drugs.  Teriparatide was effective for the prevention of vertebral and overall non-vertebral fractures in osteoporotic patients but not for the prevention of site-specific non-vertebral fractures at the wrist and hip.  Level of Evidence = I.

Prosthesis Fixation Following Total Knee Replacement

Ledin and colleagues (2017) noted that aseptic loosening is a main cause of late revision in total knee replacement (TKR).  Teriparatide stimulates osteoblasts and has been suggested to improve cancellous bone healing in humans.  This might also be relevant for prosthesis fixation.  In a RCT with blind evaluation, these researchers employed radio-stereometric analysis (RSA) to examine if teriparatide influences prosthesis fixation.  Early migration as measured by RSA can predict future loosening.  A total of 50 patients with osteoarthritis (OA) of the knee were allocated to a teriparatide treatment group (Forteo, 20 μg daily for 2 months post-operatively) or to an untreated control group; RSA was performed post-operatively and at 6 months, 12 months, and 24 months.  The primary effect variable was maximal total point motion (MTPM) from 12 to 24 months.  Median MTPM from 12 to 24 months was similar in the 2 groups (teriparatide: 0.14 mm, 10 % and 90 % percentiles: 0.08 and 0.24; control: 0.13 mm, 10 % and 90 % percentiles: 0.09 and 0.21).  The 95 % confidence interval (CI) for the difference between group means was -0.03 to 0.04 mm, indicating that no difference occurred.  The authors reported that contrary to expectation, they were unable to demonstrate any effects of teriparatide treatment on prosthesis migration at any time-point.  Moreover, the CI for the difference between group means excluded any meaningful differences.

Spinal Fusion

In a systematic review and network meta-analysis, Cheng and colleagues (2020) examined the effectiveness of teriparatide and bisphosphonate on fusion surgery of thoracic and lumbar spine.  These investigators searched Embase and PubMed for RCTs and prospective comparative studies using teriparatide or bisphosphonate in peri-operative spinal fusion surgery.  They synthesized data of fusion rate, Oswestry disability index (ODI), and AE in contrast-based network meta-analysis; pooled results were presented in risk ratio (RR) or MD)with 95 % CI.  These researchers retrieved 8 RCTs and 3 prospective studies with 676 patients undergoing spinal surgery.  Pooled result showed that teriparatide plus denosumab led to significantly higher fusion rate than placebo (RR, 2.84; 95 % CI: 1.22 to 6.60) and bisphosphonate (RR, 2.59; 95 % CI: 1.13 to 5.96).  However, they did not observe significant finding among placebo, teriparatide, and bisphosphonate in the 2 network models.  The authors concluded that this was the 1st network meta-analysis providing an overview of the use of teriparatide and bisphosphonate for spinal fusion surgery. These investigators stated that teriparatide tended to improve clinical symptoms or decrease AEs; however, the differences did not reach statistical significance.  Combined use of denosumab and teriparatide may result in better fusion rate compared with using teriparatide alone, yet more evidence is needed to support this combination therapy.

The authors stated that this study was limited by variations in follow-up duration and small number of included studies.  Even without inconsistency and concerned heterogeneity detected, the evidence obtained may be not of high quality due to the mixed sample of randomized clinical trials and prospective comparative studies.  Moreover, the consistency model of fusion rate used was an incomplete network meta-analysis.  There was only 1 trial implementing combination of teriparatide and denosumab, and the estimates of the combination treatment relied only on this single trial.  No randomized clinical trial or prospective comparative study comparing the combination therapy and bisphosphonate was found.  To confirm the efficacy of teriparatide and bisphosphonate following spinal fusion, more well-designed randomized clinical trials on this topic with multiple arms should be examined.  No recommendation on the dose of peri-operative teriparatide and duration of use can be given.  Such would merit further investigation.

Soldozy and co-workers (2020) noted that as the ageing population continues to grow, the incidence of osteoporosis continues to rise.  Patients with osteoporosis are often managed pharmacologically.  It is unclear the impact of these medications on osteoporotic patients requiring lumbar interbody fusion (LIF), and whether differences exist with respect to patient outcomes among the different medication classes that are often employed.  In a systematic review, these researchers examined studies assessing the impact of pharmacologic therapy on osteoporotic patients undergoing LIF.  Using PubMed and Medline data-bases, these investigators conducted a systematic literature review for studies published between 1986 and 2020 following PRISMA guidelines; a total of 12 articles were ultimately selected.  Studies evaluating bisphosphonate usage, PTH analogs, vitamin D, or combination therapies and their impact on LIF were included.  The authors concluded that the evidence regarding bisphosphonate therapy and improved fusion rates with reduced incidence of complications was inconsistent.  While some studies suggested bisphosphonates to confer added benefit, other studies suggested no such improvements despite reduction in bone turnover biomarkers.  Teriparatide, on the other hand, consistently demonstrated improved fusion rates and may reduce screw loosening events.  In comparison studies against bisphosphonates, teriparatide demonstrated greater potential.  A single study reported vitamin D3 to increase fusion rates, although more studies are needed to validate this finding.  These researchers noted that it is important to note that these benefits were only demonstrated in single-level fusion, with multi-level fusions not being significantly enhanced by teriparatide therapy; and combination therapy with denosumab further augment fusion rates.  They stated that further prospective RCTs are needed before standardized recommendations regarding pharmacological intervention in patients undergoing LIF could be made.

Fatima and associates (2021) stated that anecdotal and limited surgical series have described the use of teriparatide for osteoporotic patients prior to spinal fusion surgery; however, there is variability in adoption of this strategy as well as consensus regarding optimal treatment duration before and after surgery.  In this study, the clinical findings on the use of teriparatide for this application were reviewed and critically examined.  These researchers carried out a systematic review of electronic data-bases using different MeSH terms from 1980 to 2020.  Pooled and subgroup analyses were conducted using fixed and random effect models based upon the heterogeneity (I2).  The results were reported as either MD or adds ratio with 95 % CI.  A total of 771 patients from 12 studies were identified; 377 patients (90.8 % women) were treated with teriparatide.  Lumbar spinal fusion rates were significantly higher among patients who received teriparatide compared to the non-teriparatide group (OR 2.15, 95 % CI: 1.56 to 2.97, p < 0.00001).  Subgroup analysis revealed that patients receiving teriparatide demonstrated 2.12-fold and 2.23-fold higher likelihood of fusion compared to those in the bisphosphonate (OR 2.12, 95 % CI: 1.45 to 3.11, p = 0.0001) and placebo (OR 2.23, 95 % CI: 1.22 to 4.08, p = 0.009) cohorts, respectively.  The treatment effect of teriparatide was associated with significantly reduced subsequent vertebral fractures (OR 0.16, 95 % CI: 0.06 to 0.41, p = 0.0002), sagittal mal-alignment (MD - 3.85, 95 % CI: -6.49 to - 1.21, p = 0.004), limb VAS (MD - 0.36, 95 % CI: - 0.64 to - 0.09, p = 0.008), and spinal VAS (MD - 0.24, 95 % CI: - 0.44 to - 0.04, p = 0.02) compared to the non-teriparatide group.  Patients using teriparatide had 30 % less likelihood of screw loosening at last follow-up compared to the non-teriparatide group; however, this was not statistically significant (OR 0.70, 95 % CI: 0.43 to 1.14, p = 0.15).  There did not exist any statistically significant difference between the 2 comparative groups in terms of pseudoarthrosis (OR 0.54, 95 % CI: 0.24 to 1.21, p = 0.13), cage subsidence (OR 1.30, 95 % CI: 0.38 to 4.52, p = 0.68), and BMD (MD 0.04, 95 % CI: - 0.19 to 0.29, p = 0.74) at last follow-up examination.  The authors concluded that this meta-analysis corroborated the effectiveness of teriparatide resulting in higher fusion rates.  Moreover, these researchers stated that further study is needed to determine the optimal duration of treatment and timing of surgery.

The authors stated that this study had several drawbacks.  First, small sample sized RCTs.  Second, the indications of surgery and also primary pathologies were not clearly identified among the included studies.  Third, the studies did not provide sufficient data regarding different surgical approaches and level of surgeries carried out.  Fourth, significant amount of heterogeneity among the included studies in terms of age, gender, and co-morbidities.  Fifth, variability in the medication type, dose, and duration of treatment.  Sixth, only 1 included study showed no significant difference in terms of screw loosening based upon gender.  However, further studies are needed to determine the difference in outcome parameters for male and female patients with osteoporosis undergoing teriparatide treatment.

Echt and co-workers (2020) noted that proximal junctional kyphosis (PJK) and proximal junctional failure (PJF) are well-known complications after long-segment fusions in the thoraco-lumbar spine of osteoporotic patients.  Recent advances in anti-resorptive and anabolic medications, instrumentation, surgical technique, and cement augmentation have all aided in the avoidance of junctional kyphosis.  In a systematic review, these investigators reviewed current literature on the prevention of PJK and PJF in the osteoporotic spine.  They carried out a literature review using the PubMed/Medline and Embase data-bases to search for the current preventive treatment methods for PJK and PJF published in the literature (1985 to present).  Inclusion criteria included: published in English, at least 1-year mean and median follow-up, pre-operative diagnosis of osteoporosis, at least 3 levels instrumented, and studies of medical treatment or surgical techniques for prevention of junctional kyphosis.  The review of the literature yielded 7 studies with low levels of evidence ranging from level II to IV.  Treatment strategies reviewed addressed prophylaxis against ligamentous failure, adjacent vertebral compression fracture, and/or bone-implant interface failure.  This included studies on the effect of osteoporosis medication, cement augmentation, multi-rod constructs, and posterior-tension band supplementation.  The authors concluded that this systematic review of the current literature determined that there were 7 studies evaluating the effect of preventative treatments of PJK/PJF in patients with osteoporosis undergoing adult spinal deformity (ASD) correction, with low levels of evidence ranging from level II to IV.  Teriparatide therapy represented the strongest evidence with statistically significant increased BMD and decreased rates of PJF compared to a control group in a non-randomized prospective comparative study, and further clinical trials are needed to confirm these findings.  Retrospective and prospective cohorts advocate cement augmentation; however, they were not compared to a control group.  Life-threatening complications from cement embolism may occur and were avoided by strategical use at the upper instrumented vertebrae (UIV) and UIV + 1.  Augmentation of the posterior tension band to the UIV + 1 through sublaminar tethers may support the spine against increased flexion loads and reduce the incidence of PJK compared to a control group; however, the clinical significance was unclear as there was no increased need for revision surgery.  These investigators stated that future guidelines for ASD correction would benefit from incorporation of BMD-adjusted alignment goals.

The authors stated that the limitations of this review included the lack of prospective randomized trials on the topic of osteoporosis and ASD surgery.  Publications included in this qualitative analysis contained methodological heterogeneity with diversity of study designs, which required each intervention to be presented separately rather than a pooled analysis.  Conclusions on long-term outcome were limited by the decision to include articles with less than 2 years follow-up; however, this strict criterion would have significantly constricted the yielded studies.  As mentioned, the study included by Viswanathan included patients with less than 1-year follow-up; however, their mean and median follow-up was 12 months.  Despite the search strategy maximized to identify relevant articles, there was some subjectivity in screening for so-called preventive treatment, and thus one could not exclude the possibility that the search strategy missed eligible trials.  However, systematic reviews of the current literature such as this emphasized the need for high-quality studies that could provide meaningful information and guidance on treatment decisions.  The importance of developing preventive treatment strategies will only become greater as the aging population increases.

Yolcu et al (2020) stated that poor bone health can create challenges in management which are amplified for patients undergoing spinal fusion.  Although previously shown to improve outcomes post-operatively, the impact of pre-operative teriparatide use on long-term complications remains unclear.  These investigators examined the complication rates within 2 years of surgery for osteoporotic and osteopenic patients using teriparatide prior to lumbar fusion procedures.  Patients with poor bone health undergoing any lumbar fusion surgery at a single institution between 2008 and 2018 were identified and subsequently divided into 2 groups as teriparatide and non-teriparatide group.  Baseline demographics, patient and surgery related factors, and 2-year complications were collected through a retrospective chart review.  Multi-variable logistic regression was performed to evaluate the association between teriparatide usage and development of any related post-operative complication.  A total of 42 and 114 patients were identified for the teriparatide and non-teriparatide groups, respectively.  The median age (inter-quartile range [IQR]) for the teriparatide group was 62 years (55.8 to 68.8), while the non-teriparatide group had a median (IQR) age of 70 years (64 to 75.8).  Overall, there were no statistically significant differences in terms of individual complications between the groups.  However, on adjusted regression analysis, teriparatide use was associated with significantly lower odds of related complications for lumbar fusion patients (p = 0.049).  The authors concluded that teriparatide use prior to lumbar fusion procedures resulted in reduced rate of osteoporosis-related complications within 2 years post-operatively.  These investigators stated that these findings suggested improved outcomes might be observed in patients with osteopenia and osteoporosis when pre-treating with teriparatide.

Wang et al (2021) compared the therapeutic effect of TPTD and zoledronic acid (ZOL) therapy on bone formation and spinal fusion in patients with osteoporosis (OP) who underwent transforaminal lumbar interbody fusion (TLIF).  On the basis of different anti-OP therapeutic options, the TPTD group was treated daily with TPTD (20 μg. ih. qd) for at least 6 months, while the ZOL group was treated with a single dose of ZOL (5 mg. ivgtt. st) post-operatively.  The visual analog scale (VAS), ODI, BMD, and concentration of bone turnover markers before, 6, and 12 months after surgery were evaluated . X-ray and three-dimensional computed tomography (3D-CT) scans were carried out at 6 and 12 months post-operatively to evaluate interbody fusion.  The number of patients in the TPTD and ZOL groups was 29 and 38 patients, respectively.  The VAS and ODI scores in both groups were significantly reduced at 6 and 12 months after TLIF.  Compared with that of baseline, the lumbar spine BMD of TPTD patients increased significantly from 0.716 ± 0.137 g/cm2 to 0.745 ± 0.124 g/cm2 and 0.795 ± 0.123 g/cm2 at 6 and 12 months, respectively, and was significantly higher than that of the ZOL group at 12 months (0.720 ± 0.128 g/cm2).  The bone formation marker, P1NP, in the TPTD group increased significantly (145.48 ± 66.64 ng/ml and 119.55 ± 88.27 ng/ml) compared with baseline (44.67 ± 25.15 ng/ml) and in the ZOL group (28.82 ± 19.76 ng/ml and 29.94 ± 20.67 ng/ml) at 6 and 12 months, respectively.  The fusion rates in the TPTD and ZOL groups were 57 % and 45 % at 6 months, without statistical significance.  However, TPTD had a more statistically significant positive influence on fusion rate than ZOL at 12 months (86 % versus 70 %).  The authors concluded that TPTD was more efficient than ZOL in bone formation and spinal fusion in OP patients who underwent TLIF.  Moreover, these researchers stated that large-scale clinical trials are needed to confirm the role of daily TPTD for patients with OP who underwent lumbar operation. 

The authors stated that this study had several drawbacks.  First, further randomized controlled trials are needed to examine the nearly constant hip BMD for 12 months, even with a substantial elevation in spinal BMD.  Second, changes in bone density caused by different lumbar spine segments measured by dual-energy X-ray absorption (DXA) before and after surgery cannot be eliminated.  Third, these investigators were not able to evaluate an unmedicated control group to further prove the effectiveness of ZOL.  However, a variety of previous studies have been performed to examine it, including the one carried out by the authors’ department, and they made certain comparisons.  Furthermore, the sample size of this retrospective cohort study may be slightly small.

Treatment of Cranio-Facial Ciliopathies

Paese et al (2022) noted that ciliopathies represent a disease class characterized by a broad range of phenotypes including polycystic kidneys and skeletal anomalies.  Ciliopathic skeletal phenotypes are among the most common and most difficult to treat due to a poor understanding of the pathological mechanisms leading to disease.  Using an avian model (talpid2) for a human ciliopathy with both kidney and skeletal anomalies (orofaciodigital syndrome 14), these researchers identified disruptions in the FGF23-PTH axis that resulted in reduced calcium uptake in the developing mandible and subsequent micrognathia.  Although pharmacotherapy with FDA-approved pan-FGFR inhibitor AZD4547 alone rescued expression of the FGF target SPRY2, it did not significantly rescue micrognathia.  In contrast, treatment with a cocktail of AZD4547 and teriparatide acetate resulted in molecular, cellular and phenotypic rescue of ciliopathic micrognathia in talpid2 mutants.  The authors concluded that these findings provided novel insight into pathological molecular mechanisms associated with ciliopathic skeletal phenotypes and a potential therapeutic strategy for a pleiotropic disease class with limited to no therapeutic options.

Treatment of Osteoporotic Vertebral Compression Fracture

In a retrospective, comparative study, Iwata and co-workers (2017) examined the effects of teriparatide versus a bisphosphonate on radiographic outcomes in the treatment of osteoporotic vertebral compression fractures (OVCF).  A total of 98 patients undergoing non-operative treatment for recent single-level OVCF were reviewed retrospectively; 38 patients were treated by a once-daily subcutaneous injection of 20 μg of teriparatide (TPD group), whereas 60 patients received 35 mg of alendronate weekly (BP group).  Except for these medications, the same treatment protocol was applied to both groups.  The radiographic assessments included union status, vertebral kyphosis, and mid-vertebral body height.  The rates of fracture site surgical intervention were also compared between the 2 groups.  The mean follow-up period was 27 months (median of 22.5, range of 2 to 75 months).  Cox regression analysis showed that TPD reduced the time-to-union (adjusted relative HR: 1.86, 95 % CI: 1.21 to 2.83).  The union rate at 6 months after treatment was 89 % in the TPD group and 68 % in the BP group; the surgical intervention rate was significantly higher in the TPD group (p = 0.026, adjusted odds ratio [OR]: 8.15, 95 % C.: 2.02 to 43.33).  The change in local kyphosis was 4.6° in the TPD group and 3.8° in the BP group (p = 0.495, paired t-test).  The change of mid-vertebral body height was 4.4 mm in the TPD group and 3.4 mm in the BP group (p = 0.228, paired t-test).  Fracture site surgical interventions were not needed in the TPD group; however, 2 patients in the BP group eventually underwent surgical treatment for symptomatic non-union or vertebral collapse.  The authors concluded that this retrospective study suggested that teriparatide may enhance fracture healing and improve the union rate in OVCF.

The authors stated that this study had several drawbacks.  This was a retrospective comparative study that included different sample sizes and demographics between the 2 treatment groups.  The inter-group difference in the ratio of prior bisphosphonate use was a potential source of selection bias in this study.  To adjust for heterogeneity between the 2 treatment groups, these researchers used multiple logistic regression analysis.  The biological aspects of fracture healing should be examined prospectively using bone metabolic markers, vitamin D, and parathyroid hormone (PTH) level status to determine whether the state of bone turnover was comparable between the TPD group and the BP group at baseline and to examine if treatment affected bone turnover in these patients.  Due to the nature of retrospective investigation, serum bone markers could be collected only in a very limited number of patients.  In this retrospective study, the follow-up duration after 3 months following treatment differed for each doctor.  Considering the follow-up duration differences, these investigators showed the union rate on the Kaplan-Meier survival curve as the time course of vertebral union for each medication.  An MRI study might help evaluate the early phase of fracture healing.

Kang and colleagues (2019) stated that osteoporosis is one of the most common causes of VCFs.  Teriparatide is the first anabolic agent for the treatment of osteoporosis.  These researchers examined if 3 months of TPD could be effective for patients with OVCF at the thoracolumbar spine.  They reviewed 25 patients with thoracolumbar osteoporotic compression fractures between July 2012 and October 2016 who could be followed-up for more than 1 year.  Patients were divided into 2 groups depending on the use of TPD: 14 patients received TPD through subcutaneous injection (group I); and 11 patients did not receive TPD (group II).  Demographic data, BMD, hospitalization period, changes in the VAS score, BMI, and medical history such as smoking, alcohol, diabetes, and steroid usage were reviewed.  Radiographs were also reviewed to evaluate vertebral body compression percentages and kyphotic angles.  Overall changes of VAS score between injury and follow-up were statistically improved in both groups at 2 to 3 weeks post-injury.  However, difference in VAS improvement at a specific time between the 2 groups was not statistically significant.  Overall kyphotic angle and compression percentage between injury and follow-up time were increased in group II than those in group I, although the difference between the 2 groups was not statistically significant.  The authors concluded that 3-month of TPD did not show protective effects on progression of fractured vertebral body collapse or kyphotic changes in patients with osteoporosis.  These researchers stated that further prospective studies are needed to evaluate the relative indication and effective treatment period for osteoporotic compression fracture in patients with thoracolumbar VCF.

The authors stated that this study had several drawbacks.  This was a retrospective analytic study; these investigators were unable to conduct a RCT.  Prospective studies are needed to determine the progression of vertebral collapse with longer follow-up period.  Longer period of TPD usage is also needed to determine the optimal period for fracture healing.  Long-term follow-up with many patients could powerfully analyze positive effects of TPD in conservative treatment after OVCFs.  Furthermore, only pain and radiologic factors were considered in this study; economic outcomes were not analyzed.

In an open-label, non-randomized, prospective study, Kitaguchi and associates (2019) examined the effect of once-weekly TPD administration on vertebral stability and bony union after acute osteoporotic vertebral fracture (OVF).  A total of 48 subjects with acute OVF were assigned to receive activated vitamin D3 and calcium supplementation or once-weekly subcutaneous injection of TPD (56.5 μg) in combination with activated vitamin D3 and calcium supplementation for 12 weeks.  Vertebral stability was assessed using lateral plain radiography.  Vertebral height at the anterior location (VHa) and the difference in VHa {ΔVHa = VHa (supine position) - VHa (weight-bearing position)} were measured at baseline and 12 weeks after starting treatment.  Bony union was defined as the absence of a vertebral cleft or abnormal motion (ΔVHa greater than 2 mm).  Although not significant, ΔVHa, indicating vertebral stability, tended to be lower in the TPD group at 12 weeks (p = 0.17).  As for subjects with severe osteoporosis, ΔVHa at 12 weeks was significantly lower in the TPD group than in the control group (mean ΔVHa: control group, 3.1 mm (n = 15); TPD group, 1.4 mm (n = 16); p = 0.02).  The rate of bony union was significantly higher in the TPD group than in the control group (control group, 40 %; TPD group, 81 %; p = 0.03).  The authors concluded that the findings of this study indicated that once-weekly administration of TPD promoted bony union of fractured vertebra in patients with severe osteoporosis.  This approach appeared to promote the stability of fractured vertebrae by preventing further vertebral collapse during the immediate post-injury period.

The authors stated that this study had several drawback.  First, this study was not a double-blind, randomized prospective study.  To examine the issues more precisely, a double-blind, randomized prospective study should be carried out.  However, in the design of such a study, the control group would be required to interrupt anti-osteoporotic drugs for a fixed period of time.  Termination of anti-osteoporotic drugs could cause additional vertebral fractures and would therefore be ethically unacceptable.  Second, the number of subjects in both groups was relatively small.  Unlike previous studies, these researchers excluded cases of stable acute OVF that showed no or little change in ΔVHa, thereby limiting the patient population to those with vertebral instability and decreasing the number of participants included in the study.  Third, a study period of 3 months was relatively brief.  However, pain and other symptoms caused by acute OVF normally resolve within 3 months.  Vertebral collapse is most common within 3 months of injury; it was therefore reasonable to examine the effects of TPD on vertebral fractures within a 3-month period.

Treatment of Stress Fracture

Gende and colleagues (2020) noted that pelvic stress fractures are rare and present unique challenges for medical personnel.  Delayed healing can lead to increased physical, psychological, and social stress for athletes.  Recent literature suggested effective use of teriparatide to enhance healing of delayed-union stress fractures.  These researchers presented the case of a female National Collegiate Athletic Association (NCAA) Division I gymnast who successfully returned to play after a 12-week course of teriparatide injections for an ischio-acetabular stress fracture.  

Furthermore, UpToDate reviews on “Overview of stress fractures” (deWeber, 2019), “Stress fractures of the tibia and fibula” (Fields, 2019), “Stress fractures of the metatarsal shaft” (Clugston and Hatch, 2019), and “Femoral stress fractures in adults” (Jackson, 2019) do not mention teriparatide as a therapeutic option.

Carswell and colleagues (2021) noted that stress fractures are a common and potentially debilitating overuse injury to bone and occur frequently among military recruits and athletes.  Recovery from a lower body stress fracture typically requires several weeks of physical rehabilitation.  Teriparatide is used to treat osteoporosis, prevent osteoporotic fractures, and enhance fracture healing due to its net anabolic effect on bone.  In a 2-arm, parallel, prospective, randomized controlled, ITT trial, these investigators will examine the effect of teriparatide on stress fracture healing in young, otherwise healthy adults undergoing military training.  This study will enroll Army recruits (n = 136 men and women, 18 to 40 years) with a magnetic resonance imaging (MRI) diagnosed lower body stress fracture (pelvic girdle, sacrum, coccyx, or lower limb).  Subjects will be randomized to receive either usual Army standard care, or teriparatide and usual Army standard care.  Teriparatide will be self-administered by subcutaneous injections (20 μg/day) for 16 weeks, continuing to 24 weeks where a fracture remains unhealed at week 16.  The primary outcome will be the improvement in radiological healing by 2 grades or more, or reduction to grade-0 at 8 weeks after randomization, evaluated using Fredericson grading of MRI by radiologists who are blind to the randomization.  Secondary outcomes will be time to radiological healing, assessed by MRI at 8, 10, 12, 14, 16, 20 and 24 weeks, until healed; time to clinical healing, assessed using a clinical severity score of injury signs and symptoms; time to discharge from Army physical rehabilitation; pain, assessed by VAS; health-related QOL, using the Short Form (36) Health Survey; and AEs.  Exploratory outcomes will include blood and urine biochemistry; bone density and morphology evaluated using dual-energy X-ray absorptiometry (DEXA), peripheral quantitative computed tomography (pQCT), and high-resolution pQCT; physical activity measured using accelerometers; and long-term future fracture rate.  The authors stated that this study will examine if teriparatide, in addition to standard care, is more effective for stress fracture healing than standard care alone in Army recruits who have sustained a lower body stress fracture.

Vertebral Collapse after Vertebral Fracture

Tsuchie et al (2015) noted that vertebral fracture is often seen in osteoporotic patients. Teriparatide is expected to promote bone union. These researchers evaluated the action of vertebral collapse prevention by administering teriparatide to vertebral fracture patients. A total of 34 patients with fresh vertebral fracture (48 vertebrae) participated in this study. They were administered either teriparatide (daily 20 µg/day or weekly 56.5 µg/week) or risedronate (17.5 mg/week): 10 patients (20 vertebrae) received teriparatide daily (Daily group), 11 patients (15 vertebrae) received teriparatide weekly (Weekly group), and 13 patients (14 vertebrae) received risedronate (RIS group). These investigators compared some laboratory examination items, VAS of low back pain, vertebral collapse rate and local kyphotic angle, and the cleft frequency. In addition, they evaluated 22 vertebral fracture patients (24 vertebrae) who did not take any osteoporotic medicines (Control group). There was no significant difference in any of the scores at the start of treatment. At 8 and 12 weeks after the initial visit, VAS scores in the Daily and Weekly groups were significantly lower than in the RIS group (p < 0.05). At 8 and 12 weeks, the vertebral collapse rate and local kyphotic angle in the Daily group were significantly lower than in the RIS and Control groups (p < 0.01 and p < 0.05, respectively), and those in the Weekly group were significantly lower than in the Control group (p < 0.05). The cleft frequency in the Daily group was significantly lower than in the RIS group (p < 0.05). The authors concluded that teriparatide is a promising approach for the prevention of vertebral collapse progression after vertebral fracture.


Appendix A - Clinical Reasons to Avoid Oral Bisphosphonate Therapy

  • Presence of anatomic or functional esophageal abnormalities that might delay transit of the tablet (e.g. achalasia, stricture, or dysmotility
  • Active upper gastrointestinal problem (e.g., dysphagia, gastritis, duodenitis, erosive esophagitis, ulcers)
  • Presence of documented or potential gastrointestinal malabsorption (e.g. gastric bypass procedures, celiac disease, Crohn’s disease, infiltrative disorders, etc.)
  • Inability to stand or sit upright for at least 30 to 60 minutes
  • Inability to take oral bisphosphonate at least 30 to 60 minutes before first food, drink, or medication of the day
  • Renal insufficiency (creatinine clearance < 35 mL/min)
  • History of intolerance to an oral bisphosphonate

Appendix B - Clinical Reasons to Avoid IV Bisphosphonate Therapy

  • Renal insufficiency (creatinine clearance <35 mL/min)
  • Acute renal impairment
  • History of intolerance to an IV bisphosphonate
  • Hypocalcemia

Appendix C - WHO Fracture Risk Assessment Tool

  • High FRAX fracture probability: 10-year major osteoporotic fracture risk ≥ 20% or hip fracture risk ≥ 3%.
  • 10-year probability; calculation tool available at: FRAX - Fracture Risk Assessment Tool
  • The estimated risk score generated with FRAX should be multiplied by 1.15 for major osteoporotic fracture (including fractures of the spine (clinical), hip, wrist, or humerus) and 1.2 for hip fracture if glucocorticoid treatment is greater than 7.5 mg (prednisone equivalent) per day.


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