Parathyroid hormone

Summary

Parathyroid hormone (PTH) is a synthetic peptide hormone administered by subcutaneous injection. It is approved for the treatment of osteoporosis and is being investigated as hormone replacement for hypoparathyroidism. By activating the PTH1 receptor, it stimulates bone formation and regulates calcium and phosphate balance.

Mechanism of Action

PTH binds the G protein‑coupled PTH1 receptor on osteoblasts, renal tubular cells and other target tissues. In bone, intermittent activation of PTH1R raises intracellular cAMP and activates protein kinase A, promoting osteoblast activity and new bone formation while modestly increasing bone resorption. In the kidney, PTH enhances calcium reabsorption, reduces phosphate reabsorption, and stimulates 1α‑hydroxylase to increase active vitamin D, together raising serum calcium levels.

What the Research Shows

A large randomised trial in postmenopausal women with osteoporosis showed daily subcutaneous teriparatide (PTH 1‑34) reduced vertebral fractures by 65% and non‑vertebral fractures by about 50% while increasing lumbar spine BMD by up to 13% over 21 months. A network meta‑analysis of osteoporosis trials confirmed that PTH‑receptor agonists lower clinical and vertebral fracture risk more effectively than bisphosphonates. In hypoparathyroidism, phase‑2 and phase‑3 trials of the long‑acting prodrug TransCon PTH demonstrated that daily dosing restored normal serum calcium in >80% of participants, allowed independence from oral calcium and active vitamin D in >90%, and improved quality‑of‑life scores, with mild to moderate adverse events. Early phase‑1 data for the weekly prodrug MBX 2109 showed a long half‑life and tolerability but is limited to healthy volunteers.

Reported Benefits

Evidence supports teriparatide for reducing vertebral and non‑vertebral fractures and increasing bone mineral density in postmenopausal osteoporosis. In hypoparathyroidism, TransCon PTH has shown the ability to normalise serum calcium, lower urinary calcium excretion, reduce reliance on oral calcium and active vitamin D, and improve patient‑reported outcomes. Network analyses suggest PTH‑receptor agonists are more potent than anti‑resorptive agents for fracture prevention.

Limitations of the Evidence

Fracture‑reduction data pertain to daily teriparatide; newer prodrugs are still investigational and lack long‑term outcome data. The weekly MBX 2109 study involved only healthy volunteers, providing no efficacy information in disease states. Comparative trials versus other anabolic agents are limited, and safety beyond 1‑year exposure remains incompletely characterised. Regulatory approval is currently limited to the osteoporosis indication; hypoparathyroidism formulations are not yet approved.

Safety Considerations

Teriparatide was generally well tolerated, with occasional nausea, headache and rare hypercalcaemia. TransCon PTH trials reported mostly mild‑to‑moderate adverse events, including transient hypercalcaemia and reduced urinary calcium; no serious events led to discontinuation. MBX 2109’s most common effect was injection‑site irritation. Across studies, no severe or life‑threatening safety signals have emerged, but monitoring of serum calcium and renal calcium excretion is advised.

How It Is Administered

PTH products are delivered by subcutaneous injection. The approved osteoporosis formulation (teriparatide) is given daily. TransCon PTH is administered once daily in trial settings, while the investigational MBX 2109 is designed for once‑weekly subcutaneous dosing. Formulations are supplied as sterile solutions for injection; no oral or intravenous routes are described.

Routes of Administration

Goals & Uses

• Serum calcium normalizationMetabolicHigh
• Restore serum calcium in hypoparathyroidismHypocalcemiaHigh
• Bone anabolism / osteoporosis managementMusculoskeletalHigh
• Treatment of hypoparathyroidismEndocrine / Calcium HomeostasisHigh
• Reduction of supplemental calcium/vitamin D burdenQuality Of LifeModerate
• Increase bone mineral densityBone HealthHigh

Contraindications

• Conditions predisposing to osteosarcoma (e.g., Paget's disease, prior radiation to skeleton, open epiphyses)Oncologic / SkeletalHigh
• Hypersensitivity to rhPTH or excipientsAllergic / ImmunologicHigh
• HypercalcemiaMetabolic DisorderHigh
• Pre-existing hypercalcemiaMetabolicHigh
• Bone metastases or skeletal malignanciesOncologyHigh
• Malignancy or skeletal metastasesOncologicHigh
• Pediatric patients with open epiphysesPediatricHigh
• Paget disease of boneSkeletalModerate

Adverse Effects

• HypercalcemiaMetabolicCommon
• Injection site reactionsLocalCommon
• HeadacheNeurologicCommonPain in the head or upper neck
• NauseaGastrointestinalCommonFeeling of sickness or urge to vomit
• Leg crampsMusculoskeletalUncommon
• OsteosarcomaOncologyRare
• Hypocalcemia (upon discontinuation)MetabolicCommon
• DizzinessNeurologicUncommonFeeling faint, lightheaded, or unsteady

Drug Interactions

• Loop diureticsModerate
• GlucocorticoidsModerate
• Active vitamin D analogs (e.g., calcitriol)Moderate
• DigoxinHigh
• Calcium supplements / Vitamin DLow
• Calcium supplementsLow
• Thiazide diureticsModerate

Population Constraints

• PregnancyReproductive SafetyRelative
• Pediatric patientsAgeRelative
• Lactating womenReproductiveRelative
• Elderly patientsAgeRelative
• Pregnant womenReproductiveRelative
• Patients with renal impairment (severe, CrCl <30 mL/min)RenalRelative

Regulatory Status

• European UnionApprovedApproved: osteoporosis in postmenopausal women and men at high riskNatpara not approved in EU as of 2024.
• United StatesApprovedApproved: osteoporosis in postmenopausal women and men at high risk, hypoparathyroidism (Natpara)Teriparatide limited to 2 years total lifetime exposure.
• United KingdomApprovedApproved: osteoporosisSame as EU; Natpara not marketed.

Approved in the US and EU for osteoporosis (teriparatide) and in the US for hypoparathyroidism (Natpara). Use limited to ≤2 years for osteoporosis due to osteosarcoma risk in animal studies.

Evidence & Sources

• Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis
  Journal ArticleModerateNeer RM, et al.2001-01-01T00:00:00.000000Z
• Efficacy and Safety of TransCon PTH in Adults With Hypoparathyroidism: 52-Week Results From the Phase 3 PaTHway Trial
  Journal ArticleModerateClarke BL, et al.2025-01-01T00:00:00.000000Z
• Lithium toxicity profile: a systematic review and meta-analysis
  Journal ArticleHighMcKnight RF, et al.2012-01-01T00:00:00.000000Z
• MBX 2109, A Once-Weekly Parathyroid Hormone Replacement Therapy Prodrug: Phase 1, First-In-Human, Randomized Trial
  Journal ArticleModerateCarney P, et al.2025-01-01T00:00:00.000000Z
• PaTH Forward: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial of TransCon PTH in Adult Hypoparathyroidism
  Journal ArticleModerateKhan AA, et al.2022-01-01T00:00:00.000000Z
• Fracture risk reduction and safety by osteoporosis treatment compared with placebo or active comparator in postmenopausal women: systematic review, network meta-analysis, and meta-regression analysis of randomised clinical trials
  Journal ArticleHighHändel MN, et al.2023-01-01T00:00:00.000000Z

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