Teriparatide

Mechanism

An FDA-approved daily injection of parathyroid hormone fragment for severe osteoporosis. Unlike most osteoporosis drugs that slow bone loss, this one actually builds NEW bone. It stimulates osteoblasts (bone-building cells) to create new bone tissue. Used for 2 years maximum due to theoretical osteosarcoma risk from animal studies.

Effects

## Detailed Effects — Teriparatide ### Skeletal System — Bone Formation [Tier 1] - Recombinant human PTH(1-34). The first FDA-approved anabolic bone agent (2002). - Intermittent daily dosing activates PTH1R on osteoblasts, stimulating the anabolic signaling pathway: cAMP → PKA → CREB → Runx2 → osteoblast differentiation and activity. - The key pharmacologic principle: INTERMITTENT PTH exposure is anabolic (builds bone), while CONTINUOUS PTH exposure is catabolic (destroys bone, as in hyperparathyroidism). - **Neer et al., NEJM 2001 (n=1,637)**: Landmark trial. 65% reduction in new vertebral fractures, 53% reduction in non-vertebral fractures at 21 months. BMD gains: +9.7% lumbar spine, +2.6% femoral neck. - Increases both cortical and trabecular bone — but preferentially builds trabecular bone (spine > hip). - Improves bone microarchitecture and bone quality, not just density — reduces fracture risk beyond what BMD changes alone would predict. - Effects on bone formation markers: P1NP increases 150-200% within 1-3 months, confirming robust anabolic response. ### Fracture Healing [Tier 2] - Off-label use for fracture nonunions and delayed healing — multiple case series show improved healing rates. - Aspenberg et al., JBMR 2010 (n=102): accelerated healing of distal radius fractures in postmenopausal women. - Used by some orthopedic surgeons for atypical femoral fractures (bisphosphonate-associated) to stimulate healing. ### Calcium & Phosphate Metabolism [Tier 1] - Transient hypercalcemia in 11% of patients (usually mild, peaks 4-6 hours post-injection, resolves by 16 hours). - Increases renal calcium reabsorption and intestinal calcium absorption via 1,25-dihydroxy vitamin D upregulation. - May increase serum uric acid levels. ### Hypoparathyroidism [Tier 1] - FDA-approved (as Natpara, PTH 1-84) for hypoparathyroidism. Teriparatide (1-34) used off-label for the same indication. - Replaces deficient PTH to normalize calcium homeostasis, reduce supplemental calcium/calcitriol requirements.

Practitioner Guide

## Practitioner Guide — Teriparatide ### Dosing & Administration - **Dose**: 20 mcg subcutaneous injection once daily. - **Device**: Forteo prefilled pen — 28 doses per pen. - **Injection site**: Thigh or abdominal wall. Rotate sites. - **Timing**: Administer at approximately the same time each day. Patient should sit or lie down for 30 minutes after first few doses (orthostatic hypotension risk). - **Duration**: FDA label states up to 2 years. Osteosarcoma box warning based on rat studies (2-year high-dose exposure); human risk considered very low — over 20 years of post-marketing surveillance has not confirmed an increased osteosarcoma risk. ### Practitioner Sequencing Strategy (Bone Agents) **CRITICAL SEQUENCING RULES — SAME AS ABALOPARATIDE:** 1. **Anabolic first (teriparatide or abaloparatide) → then antiresorptive** for high-risk patients. 2. **DATA Trial (Leder et al., Lancet 2015)**: Teriparatide + denosumab combination produced GREATER BMD gains than either agent alone — +12.9% lumbar spine, +6.3% total hip at 2 years. This is the MOST bone-building protocol studied. 3. **If patient is on bisphosphonate**: The bisphosphonate blunts teriparatide's initial anabolic response for 6-12 months. Options: (a) stop bisphosphonate and accept delayed onset, (b) add teriparatide on top (the combination still works, just less than naive use), or (c) switch to denosumab + teriparatide combination. **Teriparatide vs Abaloparatide Selection** - Teriparatide preferred when: longer safety track record matters (20+ years), glucocorticoid-induced osteoporosis (more data), hypoparathyroidism (off-label), fracture nonunion (off-label), patient preference for established agent. - Abaloparatide preferred when: hip BMD is priority, hypercalcemia sensitivity, prior teriparatide intolerance. **After Completing Teriparatide Course** - MUST transition to antiresorptive within 1 month. - Without consolidation therapy: bone loss begins immediately. Up to 50% of BMD gains can be lost within 1-2 years. - **Best consolidation**: denosumab > zoledronic acid > oral bisphosphonates. ### Fracture Nonunion Protocol (Off-Label) - Used by orthopedic surgeons for delayed union/nonunion: 20 mcg SC daily x 3-6 months. - Also used for atypical femoral fractures from bisphosphonate use. - Evidence: case series and small RCTs — not yet standard of care but increasingly adopted. ### Supplement Synergies - **Calcium**: 1,000-1,200 mg/day total. Essential. But avoid calcium supplement within 2 hours of teriparatide dose (theoretical concern about blunting the PTH pulse). - **Vitamin D3**: Maintain 25(OH)D 40-60 ng/mL. Most patients need 2,000-5,000 IU/day. - **Vitamin K2 (MK-7)**: 100-200 mcg/day. - **Magnesium**: 400 mg/day — supports vitamin D metabolism and bone mineralization. - **Weight-bearing exercise**: Walking, resistance training — mechanical loading synergizes with teriparatide's anabolic signaling. ### Storage - Forteo pen: Refrigerate (2-8°C) at all times. Do NOT freeze. - Pen is good for 28 days after first injection. - When traveling: use insulated cooler pack. Brief room temperature exposure is acceptable but avoid prolonged heat. ### Monitoring - DXA at baseline, 1 year, 2 years. - Serum calcium at 1 month (screen for hypercalcemia) and as needed. - P1NP at baseline and 3 months (confirm anabolic response — should rise dramatically). - 25(OH)D at baseline.

Dosing Protocols

Contraindications & Cautions

• hard stop — Paget disease of bone
  Teriparatide is contraindicated in Paget disease due to the pre-existing high bone turnover state and increased risk of osteosarcoma. Labeled contraindication per Forteo prescribing information.
  Action: Do not use. This is a labeled contraindication.
• hard stop — Unexplained elevated alkaline phosphatase
  Unexplained elevations of alkaline phosphatase may indicate occult metabolic bone disease or malignancy. Teriparatide use could exacerbate underlying pathology or mask developing osteosarcoma.
  Action: Do not use until ALP elevation is fully evaluated and explained.
• hard stop — Prior radiation therapy to skeleton
  Prior skeletal radiation increases osteosarcoma risk. Teriparatide further elevates this risk by stimulating osteoblast proliferation in potentially radiation-damaged bone. Labeled contraindication.
  Action: Do not use in patients with prior skeletal radiation. This is a labeled contraindication.
• hard stop — Hypercalcemia
  Teriparatide stimulates bone resorption and calcium release. Pre-existing hypercalcemia is a contraindication as PTH analog will further elevate calcium to dangerous levels. Risk of cardiac arrhythmias, renal calculi, and altered consciousness.
  Action: Do not use. Evaluate and correct hypercalcemia before considering use.
• hard stop — Open epiphyses (skeletal immaturity)
  Teriparatide is contraindicated in patients with open epiphyses due to the risk of osteosarcoma in growing bone. This includes children, adolescents, and young adults with incomplete skeletal maturation.
  Action: Do not use in patients with open epiphyses. Labeled contraindication.
• hard stop — Bone metastases or skeletal malignancy
  Teriparatide stimulates osteoblast proliferation and bone formation. In the presence of bone metastases, this could accelerate tumor growth within the skeletal compartment.
  Action: Do not use in patients with bone metastases or any skeletal malignancy.
• hard stop — Pregnancy
  No adequate human data. Animal studies showed adverse effects. Contraindicated per labeling.
  Action: Do not use during pregnancy.
• hard stop — Under 18 years of age
  Contraindicated in patients with open epiphyses due to osteosarcoma risk.
  Action: Do not provide to individuals under 18.
• caution — Use exceeding 2 years
  Teriparatide labeling limits use to a maximum of 2 years due to osteosarcoma observed in rats with long-term exposure. While the human risk appears low, the 2-year limit is a regulatory requirement.
  Action: Do not exceed 2 years of cumulative use. Transition to antiresorptive therapy (bisphosphonate or denosumab) after teriparatide course.

Evidence

• Effect of Parathyroid Hormone (1-34) on Fractures and Bone Mineral Density in Postmenopausal Women with Osteoporosis

  Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, Hodsman AB, Eriksen EF, Ish-Shalom S, Genant HK, Wang O, Mitlak BH (2001) — New England Journal of Medicine — PMID: 11373681

  Teriparatide (PTH 1-34) 20 mcg daily reduced new vertebral fractures by 65% and nonvertebral fragility fractures by 53% vs placebo over median 21 months in postmenopausal women with osteoporosis. Lumbar spine BMD increased 9.7% and femoral neck BMD increased 2.8%. First anabolic (bone-building) osteoporosis therapy, as opposed to antiresorptive agents. FDA-approved as Forteo in 2002.

  strong

Research Summary

## Research Summary — Teriparatide ### Tier 1: Randomized Controlled Trials - **Neer et al., NEJM 2001 (n=1,637)**: Pivotal trial. Teriparatide 20 mcg/day x 21 months: 65% vertebral fracture reduction, 53% non-vertebral fracture reduction vs placebo. The trial that established anabolic therapy for osteoporosis. - **Saag et al., NEJM 2007 (n=428)**: Teriparatide vs alendronate for glucocorticoid-induced osteoporosis. Teriparatide significantly superior for BMD increase and vertebral fracture reduction. - **VERO Trial (Kendler et al., Lancet 2018, n=1,360)**: First head-to-head vs antiresorptive. Teriparatide significantly reduced vertebral (56%) and clinical fractures (52%) vs risedronate in severe osteoporosis. - **DATA Trial (Leder et al., Lancet 2015, n=94)**: Teriparatide + denosumab combination produced the largest BMD gains ever reported in any osteoporosis trial: +12.9% lumbar spine, +6.3% total hip at 2 years. ### Tier 2: Systematic Reviews & Meta-Analyses - Cochrane Review (2006, updated): Strong evidence for vertebral and non-vertebral fracture reduction. - Network meta-analyses rank teriparatide among the most effective agents for fracture reduction, particularly vertebral. - 20+ years of post-marketing data: no confirmed osteosarcoma signal in humans despite the box warning (derived from rat data at 3-58x human exposure). ### Tier 3: Case Reports & Practitioner Protocols - Widely used off-label for fracture nonunion, atypical femoral fractures, and dental implant healing. - Combination with denosumab (DATA protocol) increasingly used by endocrinologists for severe osteoporosis despite being off-label. - Practitioners note the P1NP response at 3 months is a reliable indicator of therapeutic response. ### Gaps - No head-to-head RCT against romosozumab. - Repeat courses of teriparatide after a period on antiresorptive not studied in large RCTs. - Optimal fracture nonunion dosing and duration not standardized. ### Active Trials - Generic teriparatide biosimilars now available, improving access. - Ongoing studies of combination strategies and sequential therapy optimization. - Investigation of teriparatide for periprosthetic fracture healing.