9.4 Treatment Monitoring, Drug Holidays & Non-Response Evaluation
Key Takeaways
Select a follow-up interval that can inform care. Quantitative DXA comparison requires valid matching regions and the applicable LSC.
Use reference turnover markers with the laboratory method, collection conditions, renal function and clinical question in mind.
Unexpected loss or fracture warrants a review of scan validity, medication use and clinical or secondary contributors.
A bisphosphonate holiday can be appropriate after risk reassessment. Stopping denosumab requires a follow-on antiresorptive plan.
Decide what the follow-up measurement can change
Use follow-up DXA when its result is likely to influence management. ISCD individualizes the timing based on age, BMD, treatment and conditions associated with rapid change. BHOF recommends BMD testing one to two years after starting or changing therapy in its U.S. osteoporosis care setting and then at intervals based on clinical circumstances. ACR recommends one- to two-year reassessment in specified groups continuing glucocorticoids, and annual BMD can be preferred until stability at very high risk. New fractures or risks can prompt earlier clinical review.
Compare BMD at valid matching regions on the same or properly cross-calibrated systems. Use the applicable facility least significant change (LSC), in the same units as the difference. For example, a decline from 0.810 to 0.780 g/cm² is 0.030 g/cm². If the applicable 95% LSC is 0.030 g/cm², the absolute difference meets the threshold. A difference below the LSC is statistically inconclusive and does not establish zero biological change. Stable or increasing BMD without new fractures can be consistent with treatment response. Review clinical events and actual treatment use alongside the scan.
Use turnover markers for a specific decision
Total PINP reflects formation, and β-CTX-I reflects resorption. The 2025 ESCEO/IOF/IFCC consensus reaffirms total PINP and β-CTX-I as reference markers for osteoporosis in normal renal function and prefers EDTA plasma for β-CTX-I. Follow the assay and laboratory instructions, use comparable samples for serial measurements and collect β-CTX-I under standardized morning fasting conditions. Reduced renal function can affect total PINP and β-CTX-I. The consensus recommends bone-specific ALP and TRACP5b as reference markers in CKD-associated osteoporosis. Marker and DXA change thresholds answer different questions.
For example, IOF and ECTS proposed a baseline and three-month marker check to screen for poor adherence in postmenopausal women starting oral bisphosphonates. The working group's TRIO-based thresholds were decreases greater than 38% for PINP or 56% for CTX. Those numbers belong to that protocol. A small decline can trigger review of sample comparability, dosing technique and adherence. Marker results cannot establish why a patient fractured or substitute for a clinical assessment.
Evaluate unexpected findings
Significant BMD loss or a new fracture warrants review. The Endocrine Society discusses BMD loss greater than LSC over two years as possible evidence of failure in its postmenopausal setting. AACE advises reassessment with significant bone loss or recurrent fractures, and considers two or more fragility fractures evidence of failure. A single new fracture is sufficient reason to review care.
- Check scan comparability and actual medication use, including dose timing, administration and interruptions.
- Review the fracture mechanism, falls, nutrition and interval conditions or medicines.
- Select tests for possible secondary causes based on the findings. For example, interpret elevated calcium with PTH, kidney function and vitamin D. Use targeted diagnostic evaluation rather than assuming a specific cause.
Reassess before pausing or changing therapy
| Situation | Decision |
|---|---|
| Five years of oral bisphosphonate or three years of annual IV zoledronic acid | ASBMR advises reassessing risk. Consider age, hip BMD, major osteoporotic fractures, fractures on treatment and current risks. |
| No longer high risk after bisphosphonate reassessment | A monitored holiday can be reasonable. ASBMR discusses a two- to three-year pause in selected patients. Interval and reassessment depend on risk and the agent. |
| Risk remains high after initial bisphosphonate course | Consider continued treatment or a change. Evidence for up to ten years of oral alendronate or six years of annual zoledronic acid includes vertebral outcomes from FLEX and HORIZON extensions. |
| Denosumab treatment | Maintain timely dosing while continuing therapy. If stopping, arrange a follow-on antiresorptive plan. A bisphosphonate-style holiday is unsuitable. |
During a bisphosphonate pause, reassess for new fractures, significant BMD loss and other changes in risk. Use those findings to review whether treatment should resume. A single universal CTX threshold does not determine restart. FLEX and the HORIZON extension showed residual effects in some patients, alongside vertebral fracture benefits of continued therapy in the studied populations.
Denosumab's effect reverses after dosing stops, and vertebral fractures can occur, sometimes multiple. Prolia labeling calls for transition to an alternative antiresorptive if discontinued. ECTS proposes initiating alternative antiresorptive treatment around six months after the last injection. Selection and monitoring depend on treatment duration, renal suitability and clinical risk. A 2024 randomized trial found first-year lumbar spine BMD loss despite sequential zoledronate. In a small 2026 trial, some postmenopausal women received further zoledronate under the study protocol and BMD loss still occurred. These findings support reassessment after transition. Plan the transition and follow-up with the treating clinician.
ISCD Adult Official Positions · BHOF · ACR GIOP · AACE · Endocrine Society · ASBMR task force · FLEX · HORIZON extension
2025 BTM consensus · IOF/ECTS adherence position · Prolia label · Denosumab withdrawal analysis · ECTS transition guidance · 2024 zoledronate transition trial · 2026 transition trial
A 68-year-old woman completes five years of alendronate. Her lowest valid hip T-score is −2.2, she has never fractured and a full reassessment finds she is no longer at high risk. What is a reasonable ASBMR-based approach?
Continue alendronate indefinitely because fracture risk never changes.
Consider a monitored bisphosphonate holiday and reassess if fracture risk increases.
Switch to denosumab and plan a holiday at the next dose.
Stop permanently because a higher T-score means the prior disease is cured.
A 70-year-old woman reports taking oral risedronate 35 mg weekly for two years. Comparable baseline and follow-up DXA scans show losses exceeding the respective facility least significant changes at the lumbar spine and femoral neck. She has had no new fracture. What is the appropriate next step?
This represents expected biological fluctuation; continue risedronate and re-scan in 5 years.
This confirms cure of osteoporosis; immediately discontinue all medications.
Review treatment use and administration and evaluate possible secondary contributors based on her history, examination and prior results.
This indicates immediate intolerance; double the dose of risedronate and add high-dose oral calcitonin.
A woman has taken an oral bisphosphonate for three months. Her standardized CTX falls from 500 to 400 ng/L. Under the IOF/ECTS TRIO-based oral adherence strategy, what does this change support?
An 80% decrease that establishes fracture protection.
A 20% decrease that establishes malabsorption.
A 25% decrease that meets the protocol’s CTX threshold.
A 20% decrease, below the protocol’s threshold, that can prompt review of collection and how the drug is taken.
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