Introduction
Osteoporosis in Europe
Site | At 50 years | At 80 years | ||
---|---|---|---|---|
Men | Women | Men | Women | |
Forearm | 4.6 | 20.8 | 1.6 | 8.9 |
Hip | 10.7 | 22.9 | 9.1 | 19.3 |
Spine | 8.3 | 15.1 | 4.7 | 8.7 |
Humerus | 4.1 | 12.9 | 2.5 | 7.7 |
Any of these | 22.4 | 46.4 | 15.3 | 31.7 |
Bone mineral measurements
Limitations of BMD
Diagnosis of osteoporosis
Measurement site | Technique | T-score at 60 years | WHO classification | Prevalence of osteoporosis (%) |
---|---|---|---|---|
Spine | QCT | −2.5 | Osteoporosis | 50 |
Spine | Lateral DXA | −2.2 | Low bone mass | 38 |
Spine | DXA | −1.3 | Low bone mass | 14 |
Forearm | DXA | −1. 4 | Low bone mass | 12 |
Heel | Achilles | −1.5 | Low bone mass | 11 |
Total hip | DXA | −0.9 | Normal | 6 |
Heel | Sahara | −0.7 | Normal | 3 |
Measurement of multiple skeletal sites
Osteopenia
Prevalence of osteoporosis
Age group (years) | France | UK | Germany | Italy | Spain | EU5 |
---|---|---|---|---|---|---|
50–54 | 135 | 127 | 192 | 128 | 95 | 695 |
55–59 | 200 | 175 | 265 | 180 | 126 | 974 |
60–64 | 286 | 276 | 328 | 276 | 175 | 1,385 |
65–69 | 271 | 308 | 489 | 335 | 215 | 1,672 |
70–74 | 364 | 365 | 718 | 464 | 270 | 2,236 |
75–79 | 484 | 411 | 672 | 546 | 368 | 2,543 |
80–84 | 526 | 417 | 686 | 558 | 357 | 2,612 |
50–84 | 2,266 | 2,079 | 3,350 | 2,487 | 1,606 | 12,117 |
Risk factors for fracture
BMD
Site of measurement | Outcome | |||
---|---|---|---|---|
Forearm fracture | Hip fracture | Vertebral fracture | All fractures | |
Distal radius | 1.7 (1.4–2.0) | 1.8 (1.4–2.2) | 1.7 (1.4–2.1) | 1.4 (1.3–1.6) |
Femoral neck | 1.4 (1.4–1.6) | 2.6 (2.0–3.5) | 1.8 (1.1–2.7) | 1.6 (1.4–1.8) |
Lumbar spine | 1.5 (1.3–1.8) | 1.6 (1.2–2.2) | 2.3 (1.9–2.8) | 1.5 (1.4–1.7) |
Clinical risk factors
Age |
Sex |
Low body mass index |
Previous fragility fracture, particularly of the hip, wrist and spine, including morphometric vertebral fracture in adult life |
Parental history of hip fracture |
Glucocorticoid treatment (≥5 mg prednisolone daily or equivalent for 3 months or more) |
Current smoking |
Alcohol intake 3 or more units daily |
Causes of secondary osteoporosis |
•Rheumatoid arthritis |
•Untreated hypogonadism in men and women, e.g. premature menopause, bilateral oophorectomy or orchidectomy, anorexia nervosa, chemotherapy for breast cancer, hypopituitarism, androgen deprivation therapy in men with prostate cancer |
•Inflammatory bowel disease, e.g. Crohn's disease and ulcerative colitis. It should be noted that the risk is in part dependent on the use of glucocorticoids, but an independent risk remains after adjustment for glucocorticoid exposure. |
•Prolonged immobility, e.g. spinal cord injury, Parkinson's disease, stroke, muscular dystrophy, ankylosing spondylitis |
•Organ transplantation |
•Type 1 and type 2 diabetes |
•Thyroid disorders, e.g. untreated hyperthyroidism, thyroid hormone suppressive therapy |
•Chronic obstructive pulmonary disease |
Biochemical assessment of fracture risk
Assessment of fracture risk
Introduction to FRAX
Limitations of FRAX
Dose | Prednisolone equivalent (mg/day) | Average adjustment over all ages |
---|---|---|
Hip fracture | ||
Low | <2.5 | 0.65 |
Medium | 2.5–7.5 | No adjustment |
High | ≥7.5 | 1.20 |
Major osteoporotic fracture | ||
Low | <2.5 | 0.8 |
Medium | 2.5–7.5 | No adjustment |
High | ≥7.5 | 1.15 |
Assessment of risk
Intervention thresholds
Age range (years) | 10-year fracture probability (%) | ||
---|---|---|---|
Intervention threshold | Lower assessment threshold | Upper assessment threshold | |
40–44 | 5.2 | 2.3 | 6.2 |
45–49 | 5.4 | 2.4 | 6.5 |
50–54 | 6.3 | 2.9 | 7.6 |
55–59 | 7.6 | 3.6 | 9.1 |
60–64 | 9.9 | 4.9 | 11.9 |
65–69 | 13.4 | 6.9 | 16.1 |
70–74 | 17.6 | 9.7 | 21.5 |
75–79 | 23.0 | 13.7 | 27.6 |
80–84 | 29.1 | 18.7 | 34.9 |
85–89 | 31.8 | 20.9 | 38.2 |
90–94 | 31.7 | 20.8 | 38.0 |
95–99 | 32.2 | 21.1 | 38.6 |
100+ | 32.5 | 21.3 | 39.0 |
Assessment thresholds for BMD testing
-
A threshold probability below which neither treatment nor a BMD test should be considered (lower assessment threshold)
-
A threshold probability above which treatment may be recommended irrespective of BMD (upper assessment threshold)
Application of probability thresholds
Unrestricted access to densitometry
Limited access to densitometry
No access or patchy access to densitometry
Age (years) | Gradient of risk | ||
---|---|---|---|
BMD only | Clinical risk factors alone | Clinical risk factors + BMD | |
(a) Hip fracture | |||
50 | 3.68 (2.61–5.19) | 2.05 (1.58–2.65) | 4.23 (3.12–5.73) |
60 | 3.07 (2.42–3.89) | 1.95 (1.63–2.33) | 3.51 (2.85–4.33) |
70 | 2.78 (2.39–3.23) | 1.84 (1.65–2.05) | 2.91 (2.56–3.31) |
80 | 2.28 (2.09–2.50) | 1.75 (1.62–1.90) | 2.42 (2.18–2.69) |
90 | 1.70 (1.50–1.93) | 1.66 (1.47–1.87) | 2.02 (1.71–2.38) |
(b) Other osteoporotic fractures | |||
50 | 1.19 (1.05–1.34) | 1.41 (1.28–1.56) | 1.44 (1.30–1.59) |
60 | 1.28 (1.18–1.39) | 1.48 (1.39–1.58) | 1.52 (1.42–1.62) |
70 | 1.39 (1.30–1.48) | 1.55 (1.48–1.62) | 1.61 (1.54–1.68) |
80 | 1.54 (1.44–1.65) | 1.63 (1.54–1.72) | 1.71 (1.62–1.80) |
90 | 1.56 (1.40–1.75) | 1.72 (1.58–1.88) | 1.81 (1.67–1.97) |
Alternative approaches to intervention thresholds
Other assessment models
Dubbo/Garvan | Qfracture | FRAX | |
---|---|---|---|
Externally validated | Yes (a few countries) | Yes (UK only) | Yes |
Calibrated | No | Yes (UK only) | Yes |
Applicability | Unknown | UK | 45 countries |
Falls as an input variable | Yesa
| Yes | No |
BMD as an input variable | Yes | No | Yes |
Prior fracture as an input variable | Yesa
| No | Yes |
Family history as an input variable | No | Yes | Yes |
Output | Incidence | Incidence | Probability |
Treatment responses assessed | No | No | Yes |
General management
Mobility and falls
1. | Impaired mobility, disability |
2. | Impaired gait and balance |
3. | Neuromuscular or musculoskeletal disorders |
4. | Age |
5. | Impaired vision |
6. | Neurological, heart disorders |
7. | History of falls |
8. | Medication |
9. | Cognitive impairment |
Nutrition
Major pharmacological interventions
Effect on vertebral fracture risk | Effect on non-vertebral fracture risk | |||
---|---|---|---|---|
Osteoporosis | Established osteoporosisa
| Osteoporosis | Established osteoporosisa
| |
Alendronate | + | + | NA | + (Including hip) |
Risedronate | + | + | NA | + (Including hip) |
Ibandronate | NA | + | NA | +b
|
Zoledronic acid | + | + | NA | +c
|
HRT | + | + | + | + (Including hip) |
Raloxifene | + | + | NA | NA |
Teriparatide and PTH | NA | + | NA | +d
|
Strontium ranelate | + | + | + (Including hipb) | + (Including hipb) |
Denosumab | + | +c
| + (Including hip) | +c
|
Selective oestrogen-receptor modulators
Bisphosphonates
Peptides of the parathyroid hormone family
Strontium ranelate
Denosumab
Intervention | Study | Entry criteria | Mean age (years) | Number of patients randomised | Fracture incidence (% over 3 years)a
| RR (95%CI) | |
---|---|---|---|---|---|---|---|
Placebo | Drug | ||||||
a. Vertebral fracture (high-risk population) | |||||||
Alendronate, 5–10 mg | [173] | Vertebral fractures; BMD, ≤0.68 g/m2
| 71 | 2,027 | 15.0 | 8.0 | 0.53 (0.41–0.68) |
Risedronate, 5 mg | [177] | 2 vertebral fractures or 1 vertebral fracture and T-score ≤−2.0 | 69 | 2,458 | 16.3 | 11.3 | 0.59 (0.43–0.82) |
Risedronate, 5 mg | [178] | 2 or more vertebral fractures—no BMD entry criteria | 71 | 1,226 | 29.0 | 18.0 | 0.51 (0.36–0.73) |
Raloxifene, 60 mg | [161] | Vertebral fractures—no BMD entry criteria | 66 | 7,705 | 21.2 | 14.7 | 0.70 (0.60–0.90) |
Teriparatide, 20 μg
c
| [198] | Vertebral fractures and FN or LS T-score ≤−1 if less than 2 moderate fractures | 69 | 1,637 | 14.0 | 5.0 | 0.35 (0.22–0.55) |
Ibandronate, 2.5 mg | [179] | Vertebral fractures and LS −5 < T-score ≤ −2.0 | 69 | 2,946 | 9.6 | 4.7 | 0.38 (0.25–0.59) |
Ibandronate, 20 mg | [291] | Vertebral fractures and LS −5 < T-score ≤ −2.0 | 70 | 708 | 9.6 | 4.9 | 0.50 (0.34–0.74) |
Strontium ranelate, 2 g | [201] | Vertebral fractures, LS BMD ≤0.840 g/m2
| 69 | 1,649 | 32.8 | 20.9 | 0.59 (0.48–0.73) |
Zoledronic acid, 5 mg | [185] | FN T-score ≤−2.5, ± vertebral fracture, or T-score ≤−1.5 and 2+ mild or 1 moderate vertebral fracture | 73 | 7,765 | 10.9 | 3.3 | 0.30 (0.24–0.38) |
b. Vertebral fracture (low-risk population) | |||||||
Alendronate, 5–10 mgd
| [176] | FN T-score ≤−2 | 68 | 4,432 | 3.8 | 2.1 | 0.56 (0.39–0.80) |
Alendronate, 5–10 mg d
| [176] | Subgroup of women, T-score <2.5 | NA | 1,631 | 4.0 | 2.0 | 0.50 (0.31–0.82) |
Raloxifene, 60 mg | [161] | FN or LS T-score ≤−2.5, ± vertebral fractures | 66 | 7,705 | 4.5 | 2.3 | 0.50 (0.40–0.80) |
Denosumab, 60 mg | [210] | TH or LS ≤−2.5 and >−4; 60–90 years | 72 | 7,868 | 7.2 | 2.3 | 0.32 (0.26–0.41) |
c. Hip fracture | |||||||
Alendronate, 5–0 mg | [173] | Vertebral fractures with BMD ≤0.68 g/m2
| 71 | 2,027 | 2.2 | 1.1 | 0.49 (0.23–0.99) |
Alendronate, 5–10 mg d
| [176] | FN T-score ≤−2b
| 68 | 4,432 | 0.8 | 0.7 | 0.79 (0.43–1.44) |
Alendronate, 5–10 mg d
| [176] | FN T-score ≤−2.5b (subgroup analysis) | NA | 1,631 | 1.6 | 0.7 | 0.44 (0.18–1.97) |
Risedronate, 2.5 and 5 mg | [71] | T-score <−3b or <−2b and ≥1 non-skeletal risk factor for hip fracture (subgroup analysis osteoporotic patients 70–79 years) | 77 | 9,331 | 3.2 | 1.9 | 0.60 (0.40–0.90) |
Raloxifene, 60 and 120 mg | [161] | FN or LS T-score ≤−2.5, ± vertebral fractures | 66 | 7,705 | 0.7 | 0.8 | 1.10 (0.60–1.90) |
Strontium ranelate, 2 g | [202] | Osteoporosis (T-score <−2.5) with or without prior fracture | 77 | 4,932 | 3.4 | 2.9 | 0.85 (0.61–1.19) |
Strontium ranelate, 2 g | [202] | Age ≥74 with T-score ≤−2.4b (subgroup analysis) | 80 | 1,977 | 6.4 | 4.3 | 0.64 (0.412–0.997) |
Zoledronic acid, 5 mg | [185] | FN T-score ≤−2.5 or less, ± vertebral fracture, or T-score ≤−1.5 and 2+ mild or 1 moderate vertebral fracture | 73 | 7,765 | 1.4 | 2.5 | 0.59 (0.42–0.83) |
Denosumab, 60 mg | [210] | TH or LS ≤−2.5 and >−4; age 60–90 years | 72 | 7,868 | 1.2 | 0.7 | 0.60 (0.37–0.97) |
Combination and sequential treatments
Other pharmacological interventions
Calcitonin
Hormone replacement therapy
Etidronate
Vitamin D derivatives
Clodronate
Vertebroplasty and kyphoplasty
Adherence and monitoring of treatment
Adherence to treatment
Monitoring of treatment with densitometry
Monitoring of treatment with biochemical markers of bone turnover
Investigation of patients with osteoporosis
Diagnostic workup
-
To exclude a disease which can mimic osteoporosis (e.g. osteomalacia, myelomatosis)
-
To elucidate causes of osteoporosis and contributory factors
-
To assess the severity of osteoporosis to determine the prognosis of the disease, i.e. the risk of subsequent fractures
-
To select the most appropriate form of treatment
-
To perform baseline measurements for subsequent monitoring of treatment
Routine |
History including the FRAX clinical risk factors |
Examination including height and weight |
Blood cell count, sedimentation rate, serum calcium, albumin, creatinine, phosphate, alkaline phosphatase and liver transaminases |
Lateral radiograph of lumbar and thoracic spine |
Bone densitometry (dual energy X-ray absorptiometry at hip and spine) |
Other procedures |
Lateral imaging DXA for vertebral fracture assessment (VFA) |
Markers of bone turnover, when available |
-
Establish the diagnosis of osteoporosis (e.g. DXA or X-rays)
-
Establish the cause (e.g. thyroid function tests for hyperthyroidism and urinary free cortisol for Cushing syndrome)
-
Establish differential diagnosis (e.g. protein electrophoresis for myeloma, and serum calcium and alkaline phosphatase for osteomalacia)
Differential diagnosis of osteoporosis
Health economics
Studies of intervention
Intervention | T-score = −2.5 SD | No BMD | |
---|---|---|---|
No prior fracture | Prior fracture | Prior fracture | |
Alendronate | 6,225 | 4,727 | 6,294 |
Etidronate | 12,869 | 10,098 | 9,093 |
Ibandronate daily | 20,956 | 14,617 | 14,694 |
Ibandronate intermittent | 31,154 | 21,587 | 21,745 |
Raloxifene | 11,184 | 10,379 | 10,808 |
Raloxifene without breast cancer | 34,011 | 23,544 | 23,755 |
Risedronate | 18,271 | 12,659 | 13,853 |
Strontium ranelate | 25,677 | 18,332 | 19,221 |
Strontium ranelate, post hoc analysis | 18,628 | 13,077 | 13,673 |