What is the role of recombinant parathyroid hormone (PTH) injection, such as teriparatide (parathyroid hormone), in treating severe osteoporosis in postmenopausal women and men with a history of osteoporotic fractures or low bone mass?

Role of Recombinant Parathyroid Hormone (Teriparatide) in Osteoporosis Treatment

Recombinant parathyroid hormone (teriparatide) should be reserved exclusively for postmenopausal women with primary osteoporosis at very high risk for fracture, followed immediately by bisphosphonate therapy, and is not a first-line treatment. 1

Specific Indications for Teriparatide Use

Teriparatide is FDA-approved for three specific populations at high risk for fracture or who have failed/are intolerant to other osteoporosis therapy: 2

• Postmenopausal women with osteoporosis at high risk for fracture
• Men with primary or hypogonadal osteoporosis at high risk for fracture
• Men and women with glucocorticoid-induced osteoporosis at high risk for fracture

Defining "Very High Risk" for Fracture

Very high risk is specifically defined as patients with: 1

• Recent fracture (within the past 12 months)
• History of multiple clinical osteoporotic fractures
• Multiple risk factors for fracture
• Failure of other available osteoporosis therapy (e.g., fracture occurring while on bisphosphonates)
• Older age (mean >74 years in clinical trials)

Efficacy Profile

Fracture Risk Reduction

Compared to placebo at 24 months, teriparatide demonstrates: 1

• High-certainty evidence: Reduces any clinical fractures by 27 fewer events per 1000 patients and radiographic vertebral fractures by 69 fewer events per 1000 patients
• Low-certainty evidence: May reduce clinical vertebral fractures by 45 fewer events per 1000 patients
• Low-certainty evidence: May result in no difference in hip fractures

Comparison to Bisphosphonates

When compared directly to bisphosphonates at 24 months: 1

• Moderate-certainty evidence: Probably reduces radiographic vertebral fractures by 66 fewer events per 1000 patients
• Low-certainty evidence: May reduce any clinical fracture by 46 fewer events per 1000 patients

However, bisphosphonates remain first-line therapy due to more favorable balance among benefits, harms, patient values and preferences, and cost. 3

Critical Treatment Requirements

Mandatory Sequential Therapy

This is the most important safety consideration: Teriparatide MUST be followed immediately by antiresorptive therapy (bisphosphonates or denosumab) after discontinuation. 1, 4, 3

• Discontinuation without immediate transition causes rapid bone loss and rebound vertebral fractures 4, 3
• Never discontinue teriparatide without immediately starting antiresorptive therapy 4
• This sequential therapy requirement increases the absolute cost and complexity of treatment 1

Treatment Duration Limitations

• Maximum treatment duration is 24 months during a patient's lifetime 1, 2
• Use beyond 2 years should only be considered if patient remains at or has returned to very high fracture risk 2
• The mechanism of resistance to effect after 18-24 months is not fully understood 5

Administration and Dosing

• Dose: 20 mcg subcutaneously once daily 2
• Route: Subcutaneous injection into thigh or abdominal region 2
• Initial administration: Should occur under circumstances where patient can sit or lie down if orthostatic hypotension occurs 2
• Supplementation: Consider calcium (1000-1200 mg/day) and vitamin D (600-800 IU/day) based on individual needs 4, 2

Safety Profile and Adverse Effects

Common Adverse Effects (>10%)

The most frequently reported adverse effects include: 2

• Arthralgia
• Pain
• Nausea

Other Notable Adverse Effects

Teriparatide probably increases withdrawal due to adverse effects, most commonly: 1

• Nausea, dizziness, vomiting
• Headache
• Palpitations
• Leg cramps
• Hypercalcemia 3
• Hypercalciuria 4

Serious Safety Considerations

Osteosarcoma risk: While animal studies showed increased osteosarcoma risk, postmarketing surveillance of 200,000 patients showed no significant difference in osteosarcoma incidence compared to the general population. 1, 3 However, teriparatide should be avoided in patients with: 2

• Open epiphyses (pediatric patients)
• Metabolic bone diseases including Paget's disease
• Bone metastases or history of skeletal malignancies
• Prior external beam or implant radiation therapy involving the skeleton
• Hereditary disorders predisposing to osteosarcoma

Hypercalcemia: Avoid in patients with underlying hypercalcemic disorders; discontinue if worsening cutaneous calcification develops. 2

Orthostatic hypotension: Transient orthostatic hypotension may occur with initial doses. 2

Contraindications and Special Populations

Absolute Contraindications

• Hypersensitivity to teriparatide or any excipients 2
• Patients with increased baseline risk of osteosarcoma (see above) 2

Cancer Patients

Teriparatide is best avoided in patients with history of malignancy prone to metastasize to bone. 1

• Contraindicated in patients with bone metastases, including those with potential micrometastatic or occult disease 1
• The marked increase in bone turnover may favor propagation of microscopic bone metastases through liberation of bone-derived growth factors 1
• In cases of severe osteoporosis with fractures occurring on bisphosphonate therapy in patients with remote history of cancer, teriparatide could be cautiously considered only if benefits outweigh theoretical risks 1

Urolithiasis

Consider risk/benefit carefully in patients with active or recent urolithiasis due to risk of exacerbation from hypercalciuria. 4, 2

Pregnancy and Lactation

• Consider discontinuing when pregnancy is recognized 2
• Breastfeeding is not recommended 2

Pediatric Use

Safety and effectiveness not established; avoid use due to increased baseline risk of osteosarcoma. 2

Cost Considerations

Teriparatide is the most expensive osteoporosis treatment: 3

• Average annual cost: $22,156 per Medicare beneficiary
• Approximately 4-fold more expensive than romosozumab (alternative anabolic agent at $5,574 annually) 3
• Significantly more expensive than generic bisphosphonates 4
• High acquisition cost means it should be reserved for patients at very high fracture risk or those who have failed/are intolerant to bisphosphonates 6

Clinical Decision Algorithm

When to Use Teriparatide

Use teriparatide when ALL of the following criteria are met: 1, 4

1. Patient is postmenopausal woman, man with primary/hypogonadal osteoporosis, or patient with glucocorticoid-induced osteoporosis
2. Patient meets "very high risk" criteria (see above)
3. Patient has either failed or is intolerant to bisphosphonates
4. Patient can commit to mandatory follow-on antiresorptive therapy
5. Patient has no contraindications (no history of skeletal radiation, no bone metastases, no recent cancer prone to bone metastases)

When NOT to Use Teriparatide

Avoid teriparatide when: 4

• Patient is not at very high fracture risk—use bisphosphonates instead
• Patient cannot commit to mandatory follow-on antiresorptive therapy
• Patient has contraindications listed above
• Patient has recent myocardial infarction or stroke (consider romosozumab contraindicated; teriparatide may be alternative) 3

Choosing Between Anabolic Agents

If choosing between teriparatide and romosozumab for very high-risk patients: 3

• Choose romosozumab when: No history of MI or stroke within past year, and cost is significant concern (4-fold less expensive)
• Choose teriparatide when: Recent cardiovascular events or significant cardiovascular disease present, and patient prefers self-administration at home

Common Pitfalls to Avoid

1. Never discontinue teriparatide without immediate transition to bisphosphonate or denosumab—this causes rapid bone density loss and multiple vertebral fractures 4, 3

2. Do not use as first-line therapy—bisphosphonates are first-line; teriparatide is reserved for very high-risk patients 1

3. Do not use in patients with cancer history involving bone or at risk for bone metastases—theoretical risk of promoting micrometastases 1

4. Do not exceed 24 months of treatment during patient's lifetime unless they return to very high fracture risk 2

5. Do not use in combination with bisphosphonates initially—some data suggest concurrent initiation may reduce anabolic response to PTH 5