# First-Line Pharmacotherapy for Osteoporosis in Postmenopausal Women — Endocrine Society 2020

## Bisphosphonates as First-Line Therapy

In postmenopausal women at **high risk** of fractures, the Endocrine Society recommends initial treatment with bisphosphonates to reduce fracture risk (Strong Recommendation, High-Quality Evidence, 1|++++).

### Approved Bisphosphonates

| Drug | Dose | Route | Frequency | Fracture Reduction |
|---|---|---|---|---|
| **Alendronate** | 10 mg daily or 70 mg weekly | Oral | Daily or weekly | Vertebral, hip, nonvertebral |
| **Risedronate** | 5 mg daily, 35 mg weekly, or 150 mg monthly | Oral | Daily, weekly, or monthly | Vertebral, hip, nonvertebral |
| **Zoledronic acid** | 5 mg | IV infusion | Once annually | Vertebral, hip, nonvertebral |
| **Ibandronate** | 150 mg monthly (oral) or 3 mg quarterly (IV) | Oral or IV | Monthly or quarterly | Vertebral only |

- **Ibandronate is NOT recommended** to reduce nonvertebral or hip fracture risk, as it has only demonstrated vertebral fracture reduction (Strong Recommendation, High-Quality Evidence, 1|++++).
- Alendronate, risedronate, and zoledronic acid are preferred over ibandronate because they reduce vertebral, hip, AND nonvertebral fractures.

### Oral Bisphosphonate Administration

- Take on an empty stomach with **6-8 oz (180-240 mL) plain water** first thing in the morning.
- Remain upright (sitting or standing) for at least **30 minutes** after taking the medication (60 minutes for ibandronate).
- Do not eat, drink anything other than plain water, or take other medications for at least **30 minutes** (60 minutes for ibandronate).
- These instructions reduce the risk of esophageal irritation and improve absorption.

### Contraindications and Precautions

- **Esophageal disorders** (achalasia, stricture, inability to remain upright for 30 minutes) -- contraindication to oral bisphosphonates; consider IV zoledronic acid.
- **Creatinine clearance < 30-35 mL/min** -- bisphosphonates are contraindicated; consider denosumab.
- **Hypocalcemia** -- must be corrected before initiating any bisphosphonate or denosumab.
- **Pregnancy** -- bisphosphonates are contraindicated due to potential fetal harm.

### Adverse Effects

- **Common:** Gastrointestinal symptoms (dyspepsia, esophagitis, nausea) with oral formulations; acute phase reaction (fever, myalgia, arthralgia) with IV zoledronic acid (primarily with first infusion).
- **Rare but serious:** Osteonecrosis of the jaw (ONJ) and atypical femoral fractures (AFF). The risk of ONJ and AFF is very low with osteoporosis-dose therapy (estimated ONJ: 1-10 per 100,000 patient-years; AFF: 3-50 per 100,000 patient-years) and increases with duration of therapy beyond 5 years.

## Denosumab as Alternative Initial Treatment

In postmenopausal women with osteoporosis who are at high risk for fractures, the Endocrine Society recommends denosumab as an alternative initial treatment (Strong Recommendation, High-Quality Evidence, 1|++++).

| Drug | Dose | Route | Frequency |
|---|---|---|---|
| **Denosumab** | 60 mg | Subcutaneous injection | Every 6 months |

### Key Properties of Denosumab

- Denosumab is a fully human monoclonal antibody to RANK ligand (RANKL).
- Reduces vertebral, hip, and nonvertebral fractures.
- **No renal dose adjustment required** -- can be used in patients with CKD, including those on dialysis (unlike bisphosphonates).
- Does NOT accumulate in bone; its antiresorptive effect reverses completely within 6 months of the last injection.

### Critical Warning: Denosumab Discontinuation

Administration of denosumab should **NOT be delayed or stopped** without subsequent antiresorptive (e.g., bisphosphonate, hormone therapy, or selective estrogen receptor modulator) or other therapy (Ungraded Good Practice Statement).

- Discontinuation of denosumab without follow-on therapy causes a **rapid rebound** in bone turnover markers, decrease in bone mineral density, and an **increased risk of multiple vertebral fractures**.
- The rebound effect typically occurs within **6-12 months** of the last injection.
- If denosumab must be discontinued, transition to a bisphosphonate (oral or IV) should be planned.
- A drug holiday or treatment interruption is **NOT recommended** with denosumab.

## Calcium and Vitamin D Supplementation

The guideline recommends adequate calcium and vitamin D intake as a foundation for all pharmacological osteoporosis therapies:

- **Calcium:** Total daily intake of 1,000-1,200 mg (diet plus supplements), preferring dietary sources.
- **Vitamin D:** 600-800 IU daily as a minimum; many patients require higher doses (1,000-2,000 IU/day) to achieve serum 25(OH)D levels >= 30 ng/mL.
- Correct hypocalcemia and vitamin D deficiency before starting any antiresorptive or anabolic therapy.

## Special Populations

### Renal Impairment

- **CrCl >= 35 mL/min:** All bisphosphonates may be used.
- **CrCl < 30-35 mL/min:** Bisphosphonates are contraindicated. Denosumab is the preferred option as it does not require renal dose adjustment. Monitor for hypocalcemia, which is more common in CKD patients.

### Glucocorticoid-Induced Osteoporosis

- In postmenopausal women on long-term glucocorticoids (>= 3 months at >= 5 mg/day prednisolone equivalent), the guideline supports pharmacological treatment with bisphosphonates or denosumab.
- FRAX underestimates fracture risk in patients on high-dose glucocorticoids.

## Treatment Failure on Antiresorptive Therapy

- A **single fracture** while on therapy is not necessarily evidence of treatment failure.
- **Two or more fragility fractures** occurring on therapy should be considered evidence of treatment failure.
- If treatment failure is identified, consider switching to an anabolic agent (teriparatide, abaloparatide, or romosozumab) or to an alternative antiresorptive agent.
