Osteoporosis
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osteoporosis treatment bisphosphonate
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Osteoporosis
Definition
Osteoporosis is a skeletal disorder characterized by compromised bone strength that predisposes to an increased risk of fracture. The World Health Organization (WHO) defines it as a bone mineral density (BMD) T-score of -2.5 or lower (more than 2.5 standard deviations below the mean for young normal adults). A T-score between -1.0 and -2.5 is classified as osteopenia.
- Goldman-Cecil Medicine, pp. 2607-2698
Epidemiology
- Affects approximately 200 million people worldwide, primarily postmenopausal women and older men
- Hip fractures carry the highest morbidity and mortality: ~20% of hip fracture patients die within 1 year; most of the survivors never fully regain prior function
- Vertebral fractures are clinically silent in up to 75% of patients
- Fractures of the spine, proximal femur, humerus, tibia, and pelvis are all independently associated with increased mortality
Pathophysiology
Bone undergoes continuous remodeling throughout life. Peak bone mass is achieved in the third decade; after that, there is a gradual imbalance favoring resorption over formation:
- Osteoclasts (resorption) are stimulated by RANK-L, PTH, cytokines (IL-1, IL-6, TNF)
- Osteoblasts (formation) are regulated by Wnt/beta-catenin signaling, IGF-1, and sclerostin
- After menopause, estrogen withdrawal removes its inhibitory effect on osteoclast activity, causing rapid bone loss (up to 3-5% per year in the first few years post-menopause)
- Aging reduces osteoblast function and intestinal calcium absorption, increases PTH secretion (secondary hyperparathyroidism), and increases renal calcium losses
Two main types of bone are affected differently:
- Trabecular (cancellous) bone - spine and distal radius; lost more rapidly, especially post-menopause
- Cortical bone - long bones and hip; lost more gradually with aging
Risk Factors
Major (established) risk factors:
| Category | Factors |
|---|---|
| Non-modifiable | Advanced age, female sex, White/Asian ethnicity, family history of fracture, personal history of fragility fracture |
| Modifiable | Low body weight (<57 kg), current cigarette smoking, excessive alcohol intake (>3 drinks/day), low calcium/vitamin D intake, physical inactivity |
| Medical conditions | Hypogonadism, hyperparathyroidism, hyperthyroidism, malabsorption (celiac, IBD), COPD, rheumatoid arthritis, chronic kidney disease, HIV |
| Medications | Glucocorticoids (most common iatrogenic cause), aromatase inhibitors, androgen deprivation therapy, anticonvulsants, PPIs (prolonged use), heparin |
Note: Obesity is protective due to mechanical loading and estrogen aromatization in adipose tissue.
Secondary Causes
The mnemonic "SHAMED" helps recall secondary causes:
- S - Steroid use / hyperparathyroidism
- H - Hyperthyroidism / hypogonadism
- A - Alcoholism / anticonvulsants
- M - Malabsorption
- E - Estrogen deficiency (early menopause <45 years)
- D - Diabetes (type 1)
Clinical Features
Most patients are asymptomatic until a fracture occurs. Key clinical signs:
- Height loss >2 inches from maximum height (suggests vertebral compression fractures)
- Thoracic kyphosis ("dowager's hump")
- Increased wall-to-occiput distance (reflects kyphosis severity)
- Decreased rib-to-pelvis distance
- Tenderness to palpation over spinous processes (recent vertebral fracture)
- Signs pointing to secondary causes: blue sclerae (osteogenesis imperfecta), goiter/proptosis (hyperthyroidism), facial plethora/purple striae (Cushing syndrome)
Classic fracture sites: Vertebral bodies (T8-L3), proximal femur (hip), distal radius (Colles fracture), proximal humerus. These are termed fragility fractures - fractures occurring from low-energy trauma (fall from standing height or less).
Diagnosis
Bone Mineral Density Testing
Dual-energy X-ray absorptiometry (DXA) is the gold standard:
- Measures lumbar spine, proximal femur, and distal forearm
- Low radiation, noninvasive
- T-score used in postmenopausal women and men ≥50
- Z-score used in premenopausal women and men <50 (Z-score ≤-2.0 is "below expected range for age")
WHO BMD Classification (T-scores):
| Category | T-score |
|---|---|
| Normal | ≥ -1.0 |
| Osteopenia (low bone mass) | -1.0 to -2.5 |
| Osteoporosis | ≤ -2.5 |
| Severe osteoporosis | ≤ -2.5 + fragility fracture |
Screening Recommendations
- All women ≥65 years (regardless of risk factors)
- Postmenopausal women <65 with risk factors (USPSTF)
- Men ≥70 should be considered for screening
- Any adult with a low-trauma fracture
FRAX Score
The WHO FRAX tool estimates 10-year probability of major osteoporotic fracture and hip fracture using clinical risk factors ± BMD. Treatment is generally recommended if:
- 10-year major fracture risk ≥20%, OR
- 10-year hip fracture risk ≥3%
Laboratory Workup
Used to identify secondary causes:
| Test | Purpose |
|---|---|
| Serum calcium, phosphorus | Hyperparathyroidism, osteomalacia |
| Alkaline phosphatase | Paget disease, osteomalacia |
| 25(OH) Vitamin D | Deficiency |
| PTH | Hyperparathyroidism |
| TSH | Hyperthyroidism |
| Testosterone (men) | Hypogonadism |
| CBC, CMP | Chronic disease, malnutrition |
| SPEP | Multiple myeloma |
| 24-hr urine calcium | Hypercalciuria, malabsorption |
| Celiac antibodies | Malabsorption |
Bone turnover markers (CTX for resorption, P1NP for formation) can help monitor treatment response but are not diagnostic.
Treatment
Non-Pharmacologic
- Calcium: 1,000-1,200 mg/day total (diet + supplement); food sources preferred; calcium carbonate with food; calcium citrate without food
- Vitamin D: 600-800 IU/day minimum; many guidelines suggest 1,000-2,000 IU/day to achieve serum 25(OH)D ≥20 ng/mL (≥30 ng/mL preferred by some)
- Exercise: Weight-bearing aerobic + resistance training - reduces fall risk and maintains BMD
- Fall prevention: Remove hazards, improve lighting, check vision, review medications (sedatives, antihypertensives), physical therapy, hip protectors in high-risk patients
- Lifestyle: Smoking cessation, limit alcohol (<2 drinks/day)
Pharmacologic
Antiresorptive agents (first-line):
| Drug | Class | Route | Dose | Notes |
|---|---|---|---|---|
| Alendronate | Bisphosphonate | Oral | 70 mg weekly | Must be taken fasting, remain upright 30 min |
| Risedronate | Bisphosphonate | Oral | 35 mg weekly or 150 mg monthly | Same precautions |
| Ibandronate | Bisphosphonate | Oral/IV | 150 mg monthly PO or 3 mg IV q3 months | No hip fracture data |
| Zoledronic acid | Bisphosphonate | IV | 5 mg yearly | Once-yearly infusion; reduces hip + vertebral fractures |
| Denosumab | RANK-L inhibitor | SC injection | 60 mg q6 months | Cannot stop abruptly (rebound bone loss); reduces all fracture types |
| Raloxifene | SERM | Oral | 60 mg daily | Reduces vertebral fracture + breast cancer risk; increases VTE risk; no hip fracture benefit |
Anabolic agents (for severe osteoporosis or treatment failure):
| Drug | Mechanism | Route | Notes |
|---|---|---|---|
| Teriparatide | PTH 1-34 analog | SC daily | 24 months max; stimulates bone formation; expensive |
| Abaloparatide | PTHrP 1-34 analog | SC daily | Similar to teriparatide |
| Romosozumab | Anti-sclerostin Ab | SC monthly | Dual action (anabolic + antiresorptive); 12-month course; black box warning for cardiovascular events |
Treatment threshold (ACP 2023 guidelines): Pharmacotherapy recommended for postmenopausal women and men ≥50 with osteoporosis (T-score ≤-2.5) or with prior hip/vertebral fracture. Bisphosphonates are first-line; zoledronate or denosumab for those intolerant of oral bisphosphonates.
Drug Holidays
After 3-5 years of oral bisphosphonate therapy (or 3 years of IV zoledronate), a drug holiday of 2-3 years can be considered in patients at lower risk, due to the prolonged skeletal retention of bisphosphonates. Patients at high fracture risk should continue therapy.
Special Situations
Glucocorticoid-induced osteoporosis:
- Occurs with prednisone ≥7.5 mg/day for ≥3 months
- Affects trabecular bone rapidly; fracture risk increases within months
- Prevent with calcium + vitamin D; bisphosphonate (alendronate, risedronate, or IV zoledronate) recommended if systemic corticosteroids for ≥3 months
Male osteoporosis:
- Accounts for ~20% of osteoporotic fractures
- Main causes: hypogonadism, glucocorticoids, alcohol, idiopathic
- Treatment same as for women; alendronate, risedronate, zoledronate, and teriparatide are FDA-approved in men
Monitoring
- Repeat DXA every 1-2 years during treatment; every 2 years once stable
- Bone turnover markers (CTX, P1NP) can confirm therapeutic response within 3-6 months
- Monitor calcium, 25(OH)D, and renal function periodically
Complications of Treatment
| Drug class | Complication |
|---|---|
| Bisphosphonates | Esophageal irritation/ulceration (oral); osteonecrosis of the jaw (ONJ); atypical femur fractures (rare, with prolonged use); acute phase reaction (IV) |
| Denosumab | Hypocalcemia; ONJ; atypical femur fractures; rebound vertebral fracture on discontinuation |
| Raloxifene | VTE, hot flashes |
| Romosozumab | Increased cardiovascular risk (black box warning) |
| Teriparatide/Abaloparatide | Hypercalcemia; dizziness; previously had black box for osteosarcoma (removed in 2020) |
Key Takeaways
- Osteoporosis is defined by T-score ≤-2.5; DXA is the diagnostic standard
- Up to 75% of vertebral fractures are clinically silent
- First-line pharmacotherapy: oral bisphosphonates (alendronate, risedronate) or IV zoledronate annually
- Anabolic therapy (teriparatide, romosozumab) is reserved for severe disease or treatment failure, followed by antiresorptive consolidation
- Denosumab cannot be stopped abruptly without transition to a bisphosphonate
- Treat secondary causes alongside primary osteoporosis management
- Current pharmacotherapy reduces subsequent fracture risk by approximately 50% and decreases mortality
Sources:
- Goldman-Cecil Medicine, Ch. 224-225 (Osteoporosis and Metabolic Bone Disease), pp. 2607-2698
- Swanson's Family Medicine Review, Block 4
Recent evidence (PubMed, 2023-2026):
- A 2024 meta-analysis (PMID 38733394) comparing denosumab vs. bisphosphonates found comparable safety profiles in primary osteoporosis
- A 2026 systematic review (PMID 41105226) addresses optimal sequential treatment strategies (e.g., anabolic-to-antiresorptive sequencing)
- A 2025 consensus statement (PMID 40335186) found antiresorptive therapy effectively reduces fracture risk while noting dental implant considerations with ONJ risk
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