“If this blog helped you out, don’t keep it to yourself—share the link on your socials!” 👍 “Like what you read? Spread the love and share this blog on your social media.” 👍 “Found this useful? Hit share and let your friends know too!” 👍 “If you enjoyed this post, please share the URL with your friends online.” 👍 “Sharing is caring—drop this link on your social media if it helped you.”

Monday, August 4, 2025

Parathyroid hormone and analogs


Definition
Parathyroid hormone (PTH) and its synthetic analogs are a class of drugs designed to mimic or modulate the activity of endogenous human PTH, a key regulator of calcium and phosphate metabolism. PTH is an 84-amino acid peptide hormone secreted by the parathyroid glands in response to low serum calcium levels. Pharmacologically, recombinant forms and analogs of PTH are utilized in conditions such as osteoporosis, hypoparathyroidism, and bone disorders, due to their ability to enhance bone turnover, stimulate osteoblast function, or restore calcium-phosphate homeostasis.

Approved agents in this class include:

  • Teriparatide (PTH 1-34)

  • Abaloparatide (PTHrP analog)

  • Palopegteriparatide (Yorvipath – long-acting analog of PTH 1-34)

  • Recombinant human PTH (1-84) (Natpara – now withdrawn in the US due to issues with delivery device)

1. Mechanism of Action

Parathyroid hormone exerts its effects through binding to PTH1 receptors, which are G-protein-coupled receptors (GPCRs) predominantly found in bone and kidney tissues. The pharmacologic effect depends on the pattern of exposure:

  • Intermittent exposure → stimulates osteoblast activity → promotes bone formation

  • Continuous exposure → stimulates osteoclast-mediated bone resorption → increases calcium mobilization

Therapeutic agents in this class leverage the anabolic window created by intermittent dosing to build bone mass, a property particularly important in osteoporosis treatment.

2. Classification and Drug Profiles

DrugTypeIndicationBrand Name
TeriparatideRecombinant human PTH (1-34)OsteoporosisForteo, Bonsity
AbaloparatideSynthetic analog of PTHrP (1-34)Osteoporosis (postmenopausal women)Tymlos
PalopegteriparatideLong-acting pegylated PTH analogHypoparathyroidismYorvipath
Recombinant human PTH (1-84)Full-length PTHHypoparathyroidism (discontinued)Natpara



3. Approved Indications

Teriparatide

  • Treatment of osteoporosis in postmenopausal women at high risk of fracture

  • Men with primary or hypogonadal osteoporosis

  • Glucocorticoid-induced osteoporosis

Abaloparatide

  • Postmenopausal women with osteoporosis at high risk of fracture

Palopegteriparatide

  • Long-term treatment of chronic hypoparathyroidism in adults

rhPTH (1-84) (Natpara – withdrawn)

  • Adjunct to calcium and vitamin D in hypoparathyroidism

4. Pharmacokinetics

AgentOnset of ActionPeak Plasma TimeHalf-lifeElimination
TeriparatideRapid~30 minutes~1 hourRenal
AbaloparatideRapid~1 hour~1.7 hoursHepatic/renal
PalopegteriparatideDelayed~24 hours~15–20 hoursNot fully defined


PTH analogs are administered subcutaneously, and teriparatide and abaloparatide require daily dosing, whereas palopegteriparatide is dosed once daily but has sustained effects due to its prolonged half-life and pegylation.

5. Dosage and Administration

DrugRecommended DoseRouteDuration
Teriparatide20 mcg once dailySubcutaneous (thigh or abdomen)Up to 2 years (lifetime limit)
Abaloparatide80 mcg once dailySubcutaneous (abdomen only)Up to 2 years
Palopegteriparatide21 mcg once dailySubcutaneousChronic use for hypoparathyroidism


Teriparatide and abaloparatide are self-administered using prefilled pens.

Palopegteriparatide (Yorvipath) also comes in an auto-injector pen.

6. Mechanism of Benefit in Disease States

In Osteoporosis

  • Increases bone mineral density (BMD)

  • Improves trabecular architecture

  • Decreases vertebral and non-vertebral fractures

  • Works best in high-risk patients or when antiresorptive therapy fails

In Hypoparathyroidism

  • Replaces endogenous PTH to normalize:

    • Serum calcium

    • Serum phosphate

    • Urinary calcium excretion

  • Reduces the need for active vitamin D and calcium supplements

7. Adverse Effects

SystemCommon EffectsSerious Risks
MusculoskeletalLeg cramps, joint painOsteosarcoma (seen in rats, boxed warning)
GastrointestinalNausea, vomiting-
NeurologicDizziness, headache-
MetabolicHypercalcemia, hyperuricemiaSevere hypercalcemia
Injection sitePain, erythema-


A boxed warning for osteosarcoma exists for teriparatide and abaloparatide based on animal studies, though human risk remains unproven.

8. Contraindications

  • Paget’s disease of bone

  • Unexplained elevations of alkaline phosphatase

  • Prior radiation therapy involving the skeleton

  • Children or young adults with open epiphyses

  • History of bone malignancy

  • Hypercalcemia

Teriparatide and abaloparatide are not indicated for pediatric use or in individuals with increased baseline risk of osteosarcoma.

9. Precautions and Monitoring

ParameterMonitoring Recommendations
Serum calciumAt baseline and periodically
Serum phosphateEspecially in hypoparathyroidism
Renal functionMonitor for hypercalcemia and calcium-phosphate product
Urinary calcium excretionTo prevent nephrolithiasis in hypoparathyroid patients


Patients should also be monitored for orthostatic hypotension shortly after injection, especially during initiation.

10. Drug Interactions

Drug/ClassEffect
Digitalis (Digoxin)Increased risk of toxicity with hypercalcemia
Calcium supplementsRisk of additive hypercalcemia
Vitamin D analogsDose adjustment needed when used with PTH analogs
BisphosphonatesShould not be used concurrently; PTH therapy precedes antiresorptives
Loop diureticsMay exacerbate hypocalcemia or hypercalciuria



11. Comparative Overview

FeatureTeriparatideAbaloparatidePalopegteriparatide
TypePTH (1-34)PTHrP analogPegylated PTH (1-34)
Main UseOsteoporosisOsteoporosisHypoparathyroidism
Half-life~1 hour~1.7 hours15–20 hours
Dose20 mcg daily80 mcg daily21 mcg daily
Anabolic Bone EffectStrongStronger than teriparatideModerate (not for osteoporosis)
StorageRefrigerationRefrigerationRefrigeration



12. Treatment Duration and Limitations

  • Teriparatide and Abaloparatide: Lifetime use limited to 24 months due to osteosarcoma risk.

  • Palopegteriparatide: Long-term use allowed in chronic hypoparathyroidism.

After completing anabolic therapy for osteoporosis, most patients are transitioned to antiresorptive agents (e.g., bisphosphonates or denosumab) to maintain gains in BMD.

13. Future Developments

  • Development of oral PTH analogs is in preclinical stages.

  • Alternative delivery systems (transdermal, intranasal) under exploration.

  • Personalized approaches to therapy based on genetic predictors of response (e.g., PTH receptor polymorphisms).

  • Research on dual-acting drugs combining anabolic and antiresorptive effects.

14. Clinical Practice Considerations

  • Preferred for:

    • Severe osteoporosis with high fracture risk

    • Multiple fractures or failure of other therapies

    • Hypoparathyroidism not controlled by calcium and active vitamin D

  • Not suitable for:

    • Mild osteoporosis

    • Patients at risk for malignancies or with recent radiation exposure

    • Long-term therapy beyond 2 years unless used for hypoparathyroidism



on

No comments:

Post a Comment

Subscribe to: Post Comments (Atom)