Teriparatide
Forteo
Indications for Teriparatide
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Postmenopausal osteoporosis at high fracture risk | Postmenopausal women with prior fracture, multiple risk factors, or failure/intolerance of other therapies | Monotherapy | FDA Approved |
| Male osteoporosis — primary or hypogonadal | Men at high fracture risk who have failed or are intolerant to other therapies | Monotherapy | FDA Approved |
| Glucocorticoid-induced osteoporosis | Men and women on sustained glucocorticoids (≥5 mg/day prednisone equivalent) at high fracture risk | Monotherapy | FDA Approved |
Teriparatide is the first FDA-approved anabolic bone agent (November 2002). Unlike antiresorptive therapies that slow bone breakdown, teriparatide stimulates new bone formation, making it particularly valuable for patients with severe osteoporosis, prior fractures, or inadequate response to bisphosphonates or denosumab. The AACE/ACE 2020 guidelines recommend anabolic therapy as first-line treatment for patients at very high fracture risk, including those with recent vertebral fractures, very low T-scores (below −3.0), or high FRAX scores.
Fracture healing acceleration: Small studies suggest teriparatide may accelerate healing of osteoporotic fractures (particularly vertebral and pelvic insufficiency fractures), but robust RCT evidence is limited. Evidence quality: Low to Moderate.
Hypoparathyroidism: While PTH 1-84 (natpara) is specifically approved for this indication, teriparatide has been used off-label in some centers. Evidence quality: Moderate (based on case series and open-label studies).
Dosing
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Postmenopausal osteoporosis — high fracture risk | 20 mcg SC once daily | 20 mcg SC once daily | 20 mcg/day | Inject into thigh or abdomen; supplement Ca + vit D if dietary intake is inadequate Self-administered using prefilled pen; store refrigerated 2–8°C |
| Male osteoporosis — primary or hypogonadal | 20 mcg SC once daily | 20 mcg SC once daily | 20 mcg/day | Same dose as for postmenopausal women; systemic exposure ~20–30% lower in men but no dose adjustment required |
| Glucocorticoid-induced osteoporosis — high fracture risk | 20 mcg SC once daily | 20 mcg SC once daily | 20 mcg/day | For patients on ≥5 mg/day prednisone equivalent; supplement Ca 1000 mg + vit D 800 IU daily (per GIO trial protocol) Superior to alendronate for vertebral fracture prevention in GIO (Saag 2007) |
| Severe renal impairment (CrCl <30 mL/min) | 20 mcg SC once daily (use caution) | 20 mcg SC once daily | 20 mcg/day | AUC increased by 73% and t½ by 77%; no formal dose adjustment, but risk of worsening underlying metabolic bone disease is unknown Not studied in dialysis patients |
The standard treatment course is up to 2 years, after which patients should be transitioned to an antiresorptive agent (bisphosphonate or denosumab) to consolidate and maintain the BMD gains achieved during anabolic therapy. If the patient remains at or has returned to very high fracture risk, extending beyond 2 years can be considered (2024 updated labeling). Initiating antiresorptive therapy before teriparatide (e.g., prior long-term bisphosphonate use) may blunt the initial anabolic response, particularly at the hip. The “anabolic-first” strategy is increasingly preferred for very-high-risk patients.
Pharmacology
Mechanism of Action
Teriparatide is the recombinant form of the first 34 amino acids of endogenous human parathyroid hormone (PTH 1-34), representing the biologically active N-terminal fragment. The key to its anabolic action lies in the pattern of systemic exposure: intermittent, once-daily injection produces a transient pulse of PTH receptor activation that preferentially stimulates osteoblastic (bone-forming) activity over osteoclastic (bone-resorbing) activity. This contrasts sharply with the continuous PTH elevation seen in hyperparathyroidism, which predominantly drives bone resorption. Teriparatide increases bone formation markers (BSAP, PICP) within the first month of therapy, with secondary increases in resorption markers following later. The net result is a positive bone balance, with new bone laid down on both trabecular and cortical surfaces. In the Fracture Prevention Trial, lumbar spine BMD increased by approximately 9% and femoral neck BMD by 3% over a median of 21 months.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Bioavailability ~95% (SC); Tmax ~30 minutes; peak then declines to undetectable within 3 hours | Rapid absorption and clearance creates the transient PTH pulse required for anabolic effect; inject at consistent time daily |
| Distribution | Vd ~0.12 L/kg (IV); MW 4117.8 Da | Small peptide with limited distribution beyond vascular/extracellular compartments; not expected to accumulate in bone or tissues |
| Metabolism | Non-specific enzymatic proteolysis in liver (likely Kupffer cells); fragments cleared renally; no CYP involvement | Minimal drug-drug interaction potential at the metabolic level; hepatic impairment not formally studied but hepatic clearance is only one component |
| Elimination | t½ ~1 hour (SC); systemic clearance ~62 L/hr (women), ~94 L/hr (men) — exceeds hepatic plasma flow; CrCl <30: AUC ↑73%, t½ ↑77% | Very short half-life means no accumulation with once-daily dosing; clearance involves both hepatic and extrahepatic mechanisms; exercise caution in severe renal impairment |
Side Effects
Safety data below are from the two principal osteoporosis trials in postmenopausal women and men (N = 691 teriparatide vs 691 placebo; median treatment 11–19 months) and the GIO trial (N = 214 teriparatide vs 214 alendronate active control; 18 months), as reported in the FDA prescribing information (2024).
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Pain (generalized) | 21.3% vs 20.5% placebo | Minimal excess over placebo; largely attributable to underlying disease population |
| Arthralgia | 10.1% vs 8.4% placebo | Manage symptomatically; does not typically necessitate discontinuation |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Rhinitis | 9.6% vs 8.8% placebo | Generally mild upper respiratory symptoms |
| Asthenia / Fatigue | 8.7% vs 6.8% placebo | May overlap with orthostatic hypotension episodes in early treatment |
| Nausea | 8.5% vs 6.7% placebo | More pronounced in GIO trial (14% vs 7% alendronate); usually mild and transient |
| Dizziness | 8.0% vs 5.4% placebo | May be related to transient orthostatic hypotension; counsel patients to sit/lie down for first doses |
| Headache | 7.5% vs 7.4% placebo | No meaningful difference from placebo |
| Hypertension | 7.1% vs 6.8% placebo | Marginal excess; monitor blood pressure at routine visits |
| Constipation | 5.4% vs 4.5% placebo | May be partly from concurrent calcium supplementation |
| Dyspepsia | 5.2% vs 4.1% placebo | Usually manageable with dietary modifications |
| Diarrhea | 5.1% vs 4.6% placebo | Mild and self-limited in most cases |
| Rash | 4.9% vs 4.5% placebo | Non-specific; distinguish from hypersensitivity reactions |
| Depression | 4.1% vs 2.7% placebo | Monitor mood; causality uncertain |
| Leg cramps | 2.6% vs 1.3% placebo | May relate to transient calcium shifts; ensure adequate magnesium |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Transient hypercalcemia (>ULN, 4–6 h post-dose) | 11.1% women; 6% men | 4–6 hours post-injection; resolves by 16–24 h | Typically transient and asymptomatic; if persistent on consecutive measurements (3% women, 1% men), reduce calcium supplementation and/or teriparatide dose; avoid in pre-existing hypercalcemia |
| Orthostatic hypotension (symptomatic) | 5% (PK studies) | Within 4 hours of first several doses; resolves in minutes to hours | Administer first doses where patient can sit or lie down; does not preclude continued treatment; self-limiting |
| Osteosarcoma (theoretical risk) | No increased risk observed in humans (post-marketing surveillance >500,000 patients) | N/A — seen in rats at 3–60× human exposure for nearly full lifespan | Avoid in patients at increased baseline risk for osteosarcoma (open epiphyses, Paget’s disease, skeletal malignancies, prior radiation); limit treatment to 2 years unless high-risk exceptions apply |
| Calciphylaxis / Cutaneous calcification | Rare (postmarketing) | Variable | Discontinue teriparatide immediately if worsening cutaneous calcification develops; risk factors include renal failure, autoimmune disease, warfarin, and corticosteroid use |
| Anaphylaxis / Angioedema | Rare (postmarketing) | Shortly after injection | Emergency management; permanent discontinuation; contraindication to re-exposure |
Serum calcium rises transiently 4–6 hours after each teriparatide injection and normalizes by 16–24 hours. Routine calcium monitoring should therefore be performed at least 16 hours post-dose to reflect true trough levels. Persistent hypercalcemia on consecutive measurements (uncommon: 3% women, 1% men) warrants reduction of calcium supplementation as a first step, and consideration of teriparatide dose reduction or discontinuation if unresolved. Teriparatide should not be initiated in patients with pre-existing hypercalcemia or conditions predisposing to it (e.g., primary hyperparathyroidism).
Drug Interactions
Teriparatide is a small peptide cleared by non-specific proteolysis without CYP enzyme involvement, resulting in a low potential for conventional pharmacokinetic drug-drug interactions. Clinically relevant interactions are pharmacodynamic, primarily involving calcium homeostasis.
Monitoring
- Serum CalciumBaseline; 1 month; then periodically
RoutineDraw blood at least 16 hours after last injection to avoid capturing the transient 4–6 h post-dose peak. If above ULN on consecutive measurements, reduce calcium supplementation first; consider dose reduction or discontinuation if persistent. - Serum Uric AcidBaseline; then as clinically indicated
Trigger-basedTeriparatide increases uric acid in ~3% of patients (vs 1% placebo). The hyperuricemia did not result in increased gout or urolithiasis in clinical trials, but monitor in patients with gout history. - Bone Mineral DensityBaseline; then 12–24 months
RoutineDXA at lumbar spine and hip. Expect spine BMD increase of ~9% and femoral neck ~3% over 18–21 months. DXA helps assess response and guides transition to antiresorptive therapy. - Bone Turnover MarkersBaseline; 1–3 months
Trigger-basedP1NP (procollagen type I N-terminal propeptide) is the most responsive marker. A rise of ≥10 mcg/L from baseline at 1–3 months indicates anabolic response. Useful for confirming adherence and early response. - Blood Pressure (orthostatic)At first dose; early treatment visits
Trigger-based5% of patients in short-term studies experienced symptomatic orthostatic hypotension within 4 hours of dosing. Usually occurs within first several doses and resolves without intervention. - Renal FunctionBaseline
RoutineNo dose adjustment needed, but AUC increases 73% in severe impairment (CrCl <30). Teriparatide has not been studied in dialysis; the effect on underlying metabolic bone disease in CKD is unknown. - Urolithiasis SymptomsEach visit
Trigger-basedAlthough urolithiasis rates were similar to placebo in trials, teriparatide increases urinary calcium. Consider measuring urinary calcium excretion in patients with pre-existing hypercalciuria or recent stone history.
Contraindications & Cautions
Absolute Contraindications
- Hypersensitivity to teriparatide or excipients: Postmarketing reports include anaphylaxis and angioedema.
Relative Contraindications (Specialist Input Recommended)
- Open epiphyses (pediatric / young adult patients): Increased baseline risk of osteosarcoma. Teriparatide is not approved in pediatric patients.
- Metabolic bone diseases other than osteoporosis: Including Paget’s disease of bone, which is associated with elevated baseline osteosarcoma risk.
- Bone metastases or history of skeletal malignancies: Theoretical concern about stimulating malignant bone cell activity.
- Prior external beam or implant radiation therapy involving the skeleton: Increased baseline osteosarcoma risk in irradiated bone.
- Hereditary disorders predisposing to osteosarcoma: Such as hereditary retinoblastoma.
- Pre-existing hypercalcemia or underlying hypercalcemic disorder: Including primary hyperparathyroidism; teriparatide may exacerbate hypercalcemia.
- Active or recent urolithiasis: Potential to worsen stone formation via increased urinary calcium excretion.
Use with Caution
- Patients receiving digoxin: Transient hypercalcemia may predispose to digitalis toxicity.
- Severe renal impairment (CrCl <30): AUC increased by 73%; effect on underlying CKD metabolic bone disease is unknown.
- Patients at risk of calciphylaxis: Including those with renal failure, autoimmune disease, or concomitant warfarin/corticosteroids.
- Orthostatic hypotension risk: Use caution in patients on antihypertensives; administer first doses in a supervised setting.
In Fischer 344 rats, teriparatide caused a dose-dependent increase in osteosarcoma incidence at exposures 3–60 times human exposure (based on AUC), reaching 40–50% incidence at the highest dose over a near-lifetime treatment duration. This finding has not been replicated in observational studies in humans. Two large surveillance studies (totaling >500,000 teriparatide users) found no increased osteosarcoma incidence. The FDA originally included a boxed warning based on the rat data; this was subsequently removed in the 2020 label revision (teriparatide no longer carries a boxed warning), but the osteosarcoma concern remains in the Warnings and Precautions section, and the 2-year recommended treatment limit is preserved with updated language allowing consideration of longer use in high-risk patients.
Patient Counselling
Purpose of Therapy
Teriparatide is a bone-building medicine given to strengthen your bones and reduce the risk of fractures. Unlike most osteoporosis medications that slow bone breakdown, teriparatide actively stimulates your body to form new bone. It is typically used for up to 2 years, after which your doctor will switch you to a different medication that maintains the bone you have built.
How to Take
Teriparatide is self-injected once daily under the skin of the thigh or stomach area, using a prefilled pen device. The pen must be stored in the refrigerator (not frozen) and discarded 28 days after first use. You should take your injection at a consistent time each day. For the first few doses, it is best to sit or lie down in case you feel lightheaded. Continue taking calcium and vitamin D supplements as directed by your doctor.
Sources
- Forteo (teriparatide injection) prescribing information. Eli Lilly and Company. Revised July 2024. FDA LabelPrimary source for all dosing, indications, PK data, adverse reactions (Table 1), contraindications, and osteosarcoma safety data.
- Teriparatide Injection prescribing information (generic, NDA 218771). FDA. 2024. FDA LabelGeneric teriparatide labeling confirming identical indications, dosing, and safety profile to Forteo.
- Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med. 2001;344(19):1434-1441. DOI: 10.1056/NEJM200105103441904The pivotal Fracture Prevention Trial (N = 1637) demonstrating 65% reduction in vertebral fractures and 53% reduction in nonvertebral fragility fractures with 20 mcg teriparatide over 21 months.
- Saag KG, Shane E, Boonen S, et al. Teriparatide or alendronate in glucocorticoid-induced osteoporosis. N Engl J Med. 2007;357(20):2028-2039. DOI: 10.1056/NEJMoa071408RCT (N = 428) showing teriparatide superiority over alendronate for vertebral fracture prevention (0.6% vs 6.1%) and BMD gains in glucocorticoid-induced osteoporosis.
- Orwoll ES, Scheele WH, Paul S, et al. The effect of teriparatide [human parathyroid hormone (1-34)] therapy on bone density in men with osteoporosis. J Bone Miner Res. 2003;18(1):9-17. DOI: 10.1359/jbmr.2003.18.1.9Phase 3 trial (N = 437) establishing teriparatide efficacy in men with primary or hypogonadal osteoporosis, with significant BMD gains at spine and femoral neck.
- Lindsay R, Scheele WH, Neer R, et al. Sustained vertebral fracture risk reduction after withdrawal of teriparatide in postmenopausal women with osteoporosis. Arch Intern Med. 2004;164(18):2024-2030. DOI: 10.1001/archinte.164.18.2024Follow-up study showing fracture risk reduction persists for at least 18 months after teriparatide discontinuation, supporting the concept of sequential antiresorptive consolidation therapy.
- Camacho PM, Petak SM, Binkley N, et al. American Association of Clinical Endocrinologists/American College of Endocrinology Clinical Practice Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis — 2020 Update. Endocr Pract. 2020;26(Suppl 1):1-46. DOI: 10.4158/GL-2020-0524SUPPLRecommends anabolic therapy as first-line for patients at very high fracture risk, followed by antiresorptive consolidation.
- Shoback D, Rosen CJ, Black DM, et al. Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society Guideline Update. J Clin Endocrinol Metab. 2020;105(3):dgaa048. DOI: 10.1210/clinem/dgaa048Endorses teriparatide for women at very high fracture risk and discusses the anabolic-first sequential strategy.
- Buckley L, Guyatt G, Fink HA, et al. 2017 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis. Arthritis Rheumatol. 2017;69(8):1521-1537. DOI: 10.1002/art.40137Recommends teriparatide over bisphosphonates for patients with very high fracture risk on glucocorticoids.
- Jilka RL. Molecular and cellular mechanisms of the anabolic effect of intermittent PTH. Bone. 2007;40(6):1434-1446. DOI: 10.1016/j.bone.2007.03.017Elucidates how intermittent vs continuous PTH exposure differentially regulates osteoblast and osteoclast activity.
- Satterwhite J, Heathman M, Miller PD, et al. Pharmacokinetics of teriparatide (rhPTH[1-34]) and calcium pharmacodynamics in postmenopausal women with osteoporosis. Calcif Tissue Int. 2010;87(6):485-492. DOI: 10.1007/s00223-010-9424-6Characterizes the PK/PD relationship between teriparatide exposure and transient calcium changes in the target population.
- Miller PD, Schwartz EN, Chen P, et al. Teriparatide in postmenopausal women with osteoporosis and mild or moderate renal impairment. Osteoporos Int. 2007;18(1):59-68. DOI: 10.1007/s00198-006-0189-8Demonstrates that teriparatide efficacy and safety are maintained in patients with mild-to-moderate renal impairment, with PK changes in severe impairment documented.
- Vahle JL, Zuehlke U, Schmidt A, et al. Lack of bone neoplasms and persistence of bone efficacy in cynomolgus macaques after long-term treatment with teriparatide. J Bone Miner Res. 2008;23(12):2033-2039. DOI: 10.1359/jbmr.080807Long-term primate study showing no osteosarcoma development with teriparatide, providing reassurance that the rat finding may be species-specific.