# Monitoring, Drug Holidays, and Treatment Duration — Endocrine Society 2020

## BMD Monitoring

### DXA Monitoring Schedule

- Monitor BMD in high-risk individuals with low BMD every **1 to 3 years** using DXA (Strong Recommendation, Low-Quality Evidence, 1|++OO).
- BMD monitoring should be performed at the same skeletal sites (lumbar spine, total hip, and/or femoral neck) and on the same DXA machine when possible to ensure comparability.
- A change in BMD is clinically significant only when it exceeds the **least significant change (LSC)** of the specific DXA instrument, typically **3-5%** at the lumbar spine and **4-6%** at the hip.

### When to Perform DXA

| Clinical Scenario | Recommended DXA Interval |
|---|---|
| On oral bisphosphonate therapy | Every 1-3 years |
| On IV zoledronic acid | Every 1-3 years |
| On denosumab | Every 1-2 years |
| On anabolic therapy (teriparatide, abaloparatide, romosozumab) | At end of treatment course to establish new baseline |
| During bisphosphonate drug holiday | Every 2-4 years |
| Postmenopausal women not on therapy (screening) | Per clinical judgment based on risk factors |

## Bone Turnover Markers

- Bone turnover markers (e.g., CTX for resorption, P1NP for formation) can be used to assess treatment adherence and response.
- A decrease in CTX of **>= 25-30%** from baseline within 3-6 months suggests adequate bisphosphonate or denosumab effect.
- An increase in P1NP suggests anabolic effect with teriparatide, abaloparatide, or romosozumab.
- Bone turnover markers are **not required** for routine monitoring but may be helpful in cases of suspected non-adherence or treatment failure.

## Bisphosphonate Drug Holiday

### Reassessment After Initial Treatment

The Endocrine Society recommends reassessing fracture risk after the patient has been on bisphosphonates for **3-5 years** (Strong Recommendation, Low-Quality Evidence, 1|++OO).

- For **oral bisphosphonates** (alendronate, risedronate): reassess after **5 years** of treatment.
- For **IV zoledronic acid**: a shorter reassessment period of **3 years** is more appropriate, based on RCT evidence showing residual effects after 3 years of annual use (HORIZON extension trial).

### Who Should Have a Drug Holiday

Following reassessment, prescribe a **bisphosphonate drug holiday** for women who are at **low-to-moderate** risk of fracture after the treatment period.

- The residual protective effect of bisphosphonates is due to their **long skeletal half-life** (years to decades), particularly for alendronate and zoledronic acid.
- The evidence is strongest for retention of benefits during a holiday for **alendronate** (FLEX trial) and **zoledronic acid** (HORIZON extension).
- Evidence for risedronate holiday benefit is limited; risedronate has a shorter skeletal retention than alendronate.

### Who Should NOT Have a Drug Holiday

Patients who remain at **high or very high risk** after 3-5 years of bisphosphonate therapy should **continue treatment** or be switched to an alternative agent:

- Patients with T-score <= -2.5 at the hip after treatment
- Patients with new fractures during therapy
- Patients with ongoing high-risk factors (e.g., continued glucocorticoid use, very advanced age)

### Drug Holiday Duration and Re-Initiation

- Once a bisphosphonate drug holiday is initiated, fracture risk should be reassessed at **2- to 4-year intervals**.
- Osteoporosis therapy should be **reinitiated earlier** than the suggested maximum 5-year holiday if:
  - There is a significant decline in BMD beyond the LSC of the DXA machine
  - An intervening fracture occurs
  - Bone turnover markers rise to pre-treatment levels
  - Other factors alter the clinical risk status
- The optimal duration of a bisphosphonate holiday has not been definitively established; suggested maximum is approximately **5 years** for oral bisphosphonates and **3 years** for zoledronic acid, though clinical judgment should guide individual decisions.

## Denosumab Treatment Duration

### No Drug Holiday with Denosumab

- The effects of denosumab on bone remodeling **reverse within 6 months** if the drug is not taken on schedule.
- A drug holiday or treatment interruption is **NOT recommended** with denosumab (Ungraded Good Practice Statement).
- Denosumab must be administered **every 6 months** without delay.

### Planned Discontinuation of Denosumab

If denosumab is discontinued for any reason, the following steps are recommended to mitigate rebound bone loss:

1. **Transition to a bisphosphonate** (oral or IV) to maintain BMD and prevent rebound vertebral fractures.
2. Timing: Start bisphosphonate within **6 months** of the last denosumab injection (i.e., at the time the next denosumab dose would have been due).
3. For IV zoledronic acid: a single infusion 6 months after the last denosumab dose is a commonly used approach.
4. For oral bisphosphonate: initiate at the time the next denosumab injection would have been due and continue for at least **1-2 years**.
5. Monitor BMD and bone turnover markers after transition to ensure adequate suppression of bone turnover.

## Treatment Failure Criteria

### Definition

- A **single fracture** while on approved osteoporosis therapy is not necessarily evidence of treatment failure.
- **Two or more fragility fractures** occurring during therapy should be considered evidence of treatment failure.
- A significant decline in BMD (beyond LSC) despite documented adherence may also suggest inadequate treatment response.

### Evaluation of Treatment Failure

Before concluding treatment failure, assess:

1. **Adherence:** Is the patient taking the medication correctly (timing, empty stomach for oral bisphosphonates, consistent denosumab injections)?
2. **Absorption:** Are there gastrointestinal conditions that impair oral bisphosphonate absorption (e.g., celiac disease, bariatric surgery)?
3. **Secondary causes:** Rule out newly developed secondary causes of bone loss (hyperparathyroidism, vitamin D deficiency, hyperthyroidism, multiple myeloma, celiac disease).
4. **Calcium and vitamin D status:** Are intake and serum levels adequate?

### Management of Treatment Failure

- If treatment failure is confirmed on an antiresorptive agent, switch to an **anabolic agent** (teriparatide, abaloparatide, or romosozumab).
- If treatment failure is on an anabolic agent, consider switching to a different class of anabolic or an antiresorptive.
- After the anabolic course is completed (2 years for teriparatide/abaloparatide, 12 months for romosozumab), transition to antiresorptive therapy.

## Long-Term Management Considerations

- Osteoporosis is a **chronic condition** requiring lifelong attention to fracture risk.
- There is no universally agreed-upon total treatment duration; individualized management based on ongoing fracture risk assessment is recommended.
- Patients who have been on bisphosphonate holidays should be counseled that treatment may need to be reinitiated.
- Fall prevention strategies (exercise, home safety modifications, vision correction, medication review for fall-inducing drugs) should accompany pharmacological management throughout the treatment course.

## Limitations

- The optimal duration of bisphosphonate drug holidays is uncertain; the 5-year maximum suggestion is based on limited extension trial data.
- There is no consensus on the best bone turnover marker thresholds for guiding drug holiday initiation or cessation.
- Denosumab rebound vertebral fractures after discontinuation remain an area of active investigation; the optimal transition strategy is evolving.
- Treatment failure thresholds (two or more fractures) are based on expert opinion rather than prospective validation studies.
