When Bone Loss Has a Cause to Treat
- SECONDARY osteoporosis is bone loss due to an identifiable cause (a drug or disease) rather than ageing/menopause alone; it should be suspected in men, premenopausal women, children, and anyone with disproportionately low BMD or unexplained fragility fracture.
- GLUCOCORTICOIDS are the commonest iatrogenic cause (glucocorticoid-induced osteoporosis, GIOP); bone loss and fracture risk rise EARLY (within the first months) and are partly dose- and duration-dependent, and fractures occur at a HIGHER BMD than in postmenopausal osteoporosis.
- GIOP mechanism: glucocorticoids INHIBIT Wnt and BMP signalling (diverting mesenchymal cells to ADIPOCYTES rather than osteoblasts), INCREASE the RANKL:OPG ratio (more resorption early), and cause OSTEOBLAST and OSTEOCYTE APOPTOSIS - so formation falls and resorption rises.
- Workup screens for the common secondary causes (calcium/phosphate, renal/liver function, 25-OH vitamin D, PTH, TSH, testosterone in men, coeliac serology, and myeloma screen / others as indicated) before attributing osteoporosis to ageing.
- Per the 2022 ACR guideline, adults starting or continuing GCs >=2.5 mg/day for >=3 months should have fracture-risk assessment AS SOON AS POSSIBLE (clinical assessment, BMD with vertebral fracture assessment, and FRAX if >=40), with calcium/vitamin D and lifestyle measures for all.
- Pharmacologic treatment is STRONGLY recommended for those at medium/high/very-high fracture risk: oral or IV BISPHOSPHONATES, DENOSUMAB, or PTH analogues by shared decision-making, with ANABOLIC agents conditionally favoured as initial therapy in high/very-high risk.
- “GIOP fractures occur at a HIGHER BMD than postmenopausal osteoporosis - so do not be falsely reassured by a 'less bad' T-score in a steroid-treated patient.
- “Bone loss is fastest in the FIRST few months of glucocorticoids - assess and treat EARLY, do not wait.
- “Always exclude SECONDARY causes (especially in men/premenopausal women) before labelling osteoporosis primary.
Glucocorticoids suppress bone formation (osteoblast/osteocyte apoptosis, reduced Wnt/BMP) as well as increasing early resorption; bone loss is fastest in the first months and partly dose-dependent.
Patients on glucocorticoids fracture at a higher BMD than in postmenopausal osteoporosis (bone quality, not just density, is impaired), so fracture risk is underestimated by T-score alone - assess clinical risk and treat earlier.
When to Suspect Secondary Osteoporosis
Most osteoporosis in older women is primary (postmenopausal), but you must actively look for a secondary cause when the picture is atypical: men, premenopausal women and children with osteoporosis; very low BMD or fragility fracture out of proportion to age; osteoporosis in someone on a culprit drug (especially long-term glucocorticoids); a relevant systemic disease; or ongoing bone loss / fracture despite treatment. Identifying and treating the cause is often more effective than adding another bone drug.
| 0 | 1 |
|---|---|
| Drugs | Glucocorticoids (commonest), aromatase inhibitors, androgen-deprivation therapy, anticonvulsants, PPIs (prolonged), heparin, SSRIs, thiazolidinediones |
| Endocrine | Hyperparathyroidism, hyperthyroidism, hypogonadism, Cushing syndrome, diabetes |
| Gastrointestinal | Malabsorption, coeliac disease, inflammatory bowel disease, post-bariatric, liver disease |
| Renal | Chronic kidney disease / renal osteodystrophy |
| Haematological / marrow | Multiple myeloma, mastocytosis, thalassaemia |
| Inflammatory / other | Rheumatoid arthritis and other inflammatory disease; immobilisation; alcohol excess; smoking |
Workup
Before attributing osteoporosis to age, screen for the common, treatable secondary causes (tailored to the patient): serum calcium and phosphate, renal and liver function, 25-hydroxy vitamin D, PTH, TSH, testosterone (in men), coeliac serology, and a myeloma screen (FBC/ESR, protein electrophoresis) where indicated; consider 24-hour urinary calcium, cortisol testing, and others as the history directs. Combine with BMD (DXA) with vertebral fracture assessment and FRAX to quantify risk. Finding a secondary cause changes management (treat the cause).
Glucocorticoid-Induced Osteoporosis (GIOP)
Glucocorticoids damage bone through several routes at once:
- Suppress bone formation - they inhibit Wnt/β-catenin and BMP signalling, diverting mesenchymal precursors to adipocytes rather than osteoblasts, and cause osteoblast and osteocyte APOPTOSIS.
- Increase resorption early - they raise the RANKL:OPG ratio, enhancing osteoclast maturation and activity (a relatively early, transient phase).
- Indirect effects - reduced intestinal calcium absorption, increased renal calcium loss, and hypogonadism (sex-steroid suppression). The net result is a rapid early phase of bone loss followed by ongoing formation suppression.
For adults starting or continuing GCs >=2.5 mg/day prednisolone-equivalent for >=3 months, assess fracture risk as soon as possible: clinical fracture-risk assessment, BMD with vertebral fracture assessment (or spinal X-ray), and FRAX if >=40 years (FRAX can be adjusted for GC dose). Stratify into low, medium, high or very-high fracture risk.
Because GIOP bone loss is fastest at the start, do not delay assessment and treatment until a follow-up DXA shows loss. If denosumab is used and then stopped, there is a rebound increase in resorption with risk of multiple vertebral fractures - so plan sequential therapy (e.g. transition to a bisphosphonate) rather than simply discontinuing.
Evidence & Key Studies
2022 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis
- For adults on >3 months of GCs >=2.5 mg/day, strongly recommends early fracture-risk assessment: clinical assessment, BMD with vertebral fracture assessment/spinal X-ray, and FRAX if >=40 years.
- For medium/high/very-high fracture risk, pharmacologic treatment is strongly recommended; choice of oral/IV bisphosphonate, denosumab or PTH analogue by shared decision-making.
- Anabolic agents are conditionally recommended as initial therapy for high and very-high risk; new recommendations cover discontinuation and sequential therapy.
Osteoporosis due to hormone imbalance: estrogen deficiency and glucocorticoid overuse on bone turnover
- Excess glucocorticoids interfere with the canonical BMP pathway and inhibit Wnt protein production, causing mesenchymal progenitors to differentiate to adipocytes rather than osteoblasts.
- Glucocorticoids increase the RANKL:OPG ratio (promoting osteoclast maturation/resorption) and cause osteoblast and osteocyte apoptosis, reducing formation.
- Explains why GIOP both suppresses formation and (early) increases resorption - and why avoiding excess glucocorticoid is mandatory.
According to PubMed, the assessment/treatment algorithm comes from the cited 2022 ACR practice guideline and the GIOP mechanism from the cited molecular review. The list of secondary causes and the screening panel are standard, well-established clinical practice. (See also our Osteoporosis and Bone Signaling Pathways topics.)
Clinical Decision Scenarios
Practise clinical reasoning and management decisions out loud
“A 58-year-old man on long-term prednisolone for an inflammatory condition is referred after a low-trauma vertebral fracture. How do glucocorticoids damage bone, and how would you assess and treat his osteoporosis?”
“When would you suspect a secondary cause of osteoporosis, and what would your screening workup include?”
Mnemonics & Memory Aids
STEROID
Hook:STEROID captures GIOP: suppressed formation, early loss, fracture at higher BMD, assess and treat.
SECONDARY
Hook:Think SECONDARY in the atypical patient: steroids, endocrine, coeliac, other drugs, myeloma, kidney.
Suspect secondary when
- Men, premenopausal women, children; disproportionate BMD/fracture
- On glucocorticoids or other culprit drug; relevant systemic disease
- Ongoing loss/fracture despite treatment
GIOP mechanism
- ↓Wnt/BMP + osteoblast/osteocyte apoptosis (↓formation)
- ↑RANKL:OPG (early ↑resorption); ↓Ca absorption, hypogonadism
- Fast early loss; fractures at higher BMD than postmenopausal
Workup
- Ca/PO4, renal/liver, 25-OH vit D, PTH, TSH, testosterone (men)
- Coeliac serology, myeloma screen (FBC/ESR, electrophoresis)
- DXA with vertebral fracture assessment + FRAX
GIOP management (2022 ACR)
- Assess if GC >=2.5 mg/day for >=3 months (clinical + DXA/VFA + FRAX if >=40)
- All: Ca/vit D, lifestyle, lowest effective GC dose
- Medium/high/very-high risk: bisphosphonate, denosumab or PTH analogue; anabolic conditionally first-line if high-risk; plan sequential therapy