# Anabolic Agents and Treatment Sequencing — Endocrine Society 2020

## Indications for Anabolic Therapy

In postmenopausal women with osteoporosis at **very high risk** of fracture, the Endocrine Society recommends anabolic therapy as initial treatment, rather than antiresorptive agents, for more rapid and greater fracture risk reduction.

Very high risk includes:
- Severe osteoporosis (T-score <= -2.5 **with** fragility fractures)
- Multiple vertebral fractures
- Recent fracture (within 12 months)
- Fractures while on approved osteoporosis therapy (treatment failure)
- Very low BMD (T-score <= -3.0)

## Teriparatide

In postmenopausal women with osteoporosis at very high risk of fracture, the guideline recommends teriparatide treatment for up to **2 years** for the reduction of vertebral and nonvertebral fractures (Strong Recommendation, Moderate-Quality Evidence, 1|+++O).

| Property | Detail |
|---|---|
| **Drug** | Teriparatide (recombinant human PTH 1-34) |
| **Dose** | 20 mcg |
| **Route** | Subcutaneous injection |
| **Frequency** | Once daily |
| **Maximum duration** | 2 years (cumulative lifetime exposure) |
| **Fracture reduction** | Vertebral and nonvertebral fractures |

### Adverse Effects

- Dizziness
- Leg cramps
- Transient hypercalcemia (monitor serum calcium)
- Nausea
- Orthostatic hypotension

### Contraindications

- Unexplained elevation of alkaline phosphatase
- Pre-existing hypercalcemia
- Paget disease of bone
- Prior skeletal radiation therapy
- Open epiphyses (not applicable to postmenopausal women)
- Bone metastases or skeletal malignancies
- Active or recent urolithiasis (relative contraindication)

## Abaloparatide

In postmenopausal women with osteoporosis at very high risk of fracture, the guideline recommends abaloparatide treatment for up to **2 years** for the reduction of vertebral and nonvertebral fractures (Strong Recommendation, Moderate-Quality Evidence, 1|+++O).

| Property | Detail |
|---|---|
| **Drug** | Abaloparatide (synthetic PTHrP analog) |
| **Dose** | 80 mcg |
| **Route** | Subcutaneous injection |
| **Frequency** | Once daily |
| **Maximum duration** | 2 years (cumulative lifetime exposure) |
| **Fracture reduction** | Vertebral and nonvertebral fractures |

### Adverse Effects Leading to Discontinuation

- Nausea
- Postural hypotension
- Dizziness
- Headache
- Palpitations

### Differences from Teriparatide

- Abaloparatide may cause less hypercalcemia compared to teriparatide.
- Abaloparatide has a more selective effect on the PTH1 receptor configuration that favors anabolic bone formation.

## Romosozumab (2020 Guideline Update)

In postmenopausal women with osteoporosis at very high risk of fracture, the guideline recommends romosozumab treatment for up to **1 year** for the reduction of vertebral, hip, and nonvertebral fractures (Strong Recommendation, Moderate-Quality Evidence, 1|+++O).

| Property | Detail |
|---|---|
| **Drug** | Romosozumab (anti-sclerostin monoclonal antibody) |
| **Dose** | 210 mg (administered as two 105 mg subcutaneous injections) |
| **Route** | Subcutaneous injection |
| **Frequency** | Once monthly |
| **Maximum duration** | 12 months |
| **Fracture reduction** | Vertebral, hip, and nonvertebral fractures |

### Unique Mechanism

- Romosozumab has a **dual mechanism**: it simultaneously stimulates bone formation (anabolic) and inhibits bone resorption (antiresorptive) by blocking sclerostin.
- This dual effect produces rapid and substantial gains in bone mineral density within 12 months.

### Cardiovascular Safety Warning

- **Women at high risk of cardiovascular disease or stroke should NOT be considered for romosozumab** pending further studies on cardiovascular risk.
- High cardiovascular risk includes patients with prior **myocardial infarction** or **stroke**.
- The ARCH trial (romosozumab vs. alendronate) showed a numerical imbalance in cardiovascular events in the romosozumab arm. This has not been confirmed in other trials but warrants caution.

## Treatment Sequencing: Anabolic First, Then Antiresorptive

The guideline emphasizes the importance of **sequential therapy** after completion of anabolic agents.

### After Teriparatide or Abaloparatide (up to 2 years)

In postmenopausal women who have completed a course of teriparatide or abaloparatide, the guideline recommends treatment with **antiresorptive osteoporosis therapies** (bisphosphonate or denosumab) to maintain bone mineral density gains and reduce fracture risk (Strong Recommendation, Moderate-Quality Evidence, 1|+++O).

- If anabolic therapy is discontinued without follow-on antiresorptive therapy, the bone density gains will be **rapidly lost**.
- A bisphosphonate or denosumab should be initiated promptly after the anabolic course is completed.

### After Romosozumab (12 months)

In postmenopausal women who have completed a course of romosozumab, the guideline recommends treatment with **antiresorptive osteoporosis therapies** to maintain bone mineral density gains and reduce fracture risk (Strong Recommendation, Moderate-Quality Evidence, 1|+++O).

- Transition to alendronate after romosozumab was studied in the ARCH trial and showed continued fracture risk reduction.
- Transition to denosumab after romosozumab was studied in the FRAME extension and showed further BMD gains.

### Sequencing Decision Algorithm

1. **Very high risk** --> Start with anabolic agent (teriparatide, abaloparatide for up to 2 years; OR romosozumab for up to 12 months) --> Transition to antiresorptive (bisphosphonate or denosumab).
2. **High risk** --> Start with bisphosphonate or denosumab.
3. **Treatment failure on antiresorptive** --> Switch to anabolic agent --> Then return to antiresorptive after anabolic course.

### Important Sequencing Cautions

- **Avoid starting teriparatide or abaloparatide after denosumab** without careful planning, as denosumab discontinuation can trigger rapid bone loss and vertebral fractures.
- Prior bisphosphonate use may blunt the anabolic response to teriparatide (less BMD gain compared to treatment-naive patients), though fracture reduction is still observed.
- Romosozumab appears to retain efficacy even in patients previously treated with bisphosphonates.

## Limitations

- The optimal duration and sequence of osteoporosis therapies have not been definitively established through head-to-head sequencing trials for all combinations.
- Lifetime treatment duration limits for teriparatide and abaloparatide (2 years) and romosozumab (12 months) are based on clinical trial durations and regulatory considerations, not evidence of harm beyond these periods.
- The cardiovascular safety signal for romosozumab requires further investigation.
