Overview
Osteoporosis and other metabolic bone diseases arise from disordered bone modeling or remodeling. In osteoporosis, low bone mass results from more bone being removed by osteoclast activity than formed by osteoblast activity. Trabecular bone has a higher surface area and remodels faster than cortical bone, so bone loss with increased turnover is faster in vertebrae and other trabecular-rich sites than in cortical-dominant sites such as the femoral neck. Osteoporosis presents as fragility fractures and as part of orthopaedic practice, so its evaluation, drug treatment and drug toxicity (particularly atypical femoral fractures) matter to the surgeon. (Rockwood)
Risk Factors (Rockwood Table 4-1)
Lifestyle and constitutional: smoking, excessive alcohol (more than 3 units per day), low body weight (BMI under 19), early menopause, genetic factors, ethnicity, family history of hip fracture, social deprivation. Heavy cannabis use has been associated with low bone density and increased fracture risk. Mechanical loading increases bone mass, and inactivity causes bone loss.
Diseases: thyrotoxicosis, rheumatoid arthritis and other inflammatory rheumatic diseases, primary hyperparathyroidism, Cushing syndrome, hypogonadism, anorexia nervosa, cancer, chronic liver disease, celiac disease, inflammatory bowel disease, cystic fibrosis, epilepsy.
Drugs: glucocorticoids (a strong risk factor, with risk related to dose), thyroxine (excess replacement), GnRH agonists, sedatives and benzodiazepines, SSRIs, anticonvulsants. Inhaled steroids have little effect on fracture risk. (Rockwood)
Glucocorticoids reduce intestinal calcium absorption, increase renal calcium loss, and reduce bone formation through osteoblast and osteocyte apoptosis. (Rockwood)
Evaluation
DEXA of the spine and hip is the most important test. Osteoporosis is defined as BMD 2.5 standard deviations (T-score) below young healthy adults. T-score between -1.0 and -2.5 is low bone density (osteopenia), and above -1.0 normal.
Who to scan: UK practice supports DEXA for patients over 50 with a fragility fracture, the basis of the fracture liaison service (FLS) model, which raised the proportion investigated for osteoporosis from about 10% to above 90% in one study. The US National Osteoporosis Foundation recommends DEXA for those 50 or older with an adult fracture, all women over 65, all men over 70, and those aged 50–69 with clinical risk factors.
Fracture risk calculators (FRAX, QFracture) use clinical risk factors to decide on DEXA and the benefit of treatment.
Laboratory: screen for secondary causes (including renal and liver function, calcium, vitamin D and others). Transiliac bone biopsy is rarely needed, for atypical osteoporosis or suspected infiltrative disease. Bone turnover markers (CTX, NTX, deoxypyridinoline, TRAP for resorption; total and bone-specific alkaline phosphatase, osteocalcin, PINP, PICP for formation) are not diagnostic but can aid understanding of pathophysiology. (Rockwood)
Treatment
Optimal management combines correcting modifiable lifestyle risk factors, treating secondary causes, addressing fall risk, and starting drug treatment when appropriate. The evidence base for drug treatment is strongest in patients with DEXA-proven osteoporosis. The National Osteoporosis Foundation recommends treating postmenopausal women and men 50 or older presenting with a hip or vertebral fracture, or with other risk or T-score criteria. (Rockwood)
Non-pharmacologic
Calcium and vitamin D. Recommended daily calcium intake is 1,000 mg for men and premenopausal women and 1,500 mg for postmenopausal women (per the source). Vitamin D is needed for optimal calcium absorption. Combined supplements reduce fracture risk, mostly in elderly or institutionalized patients at risk of deficiency. UK advice is 400 IU daily to maintain 25(OH)D above 50 nmol/L, and 2011 US Institute of Medicine guidance is 600 IU daily to age 70 and 800 IU above 70. Always correct vitamin D deficiency before potent antiresorptives (to reduce hypocalcemia risk).
Exercise. Programs reduce injurious falls (odds ratio 0.7) and fall-related fractures (0.39) in a meta-analysis, and improve pain and quality of life after vertebral fractures.
Smoking and alcohol. Advise cessation and alcohol below 3 units a day.
Other. Treat visual impairment (cataract surgery significantly reduced fracture rates), celiac disease, primary hyperparathyroidism and inflammatory disease. (Rockwood)
Drug therapy (antiresorptive vs anabolic)
Bisphosphonates are stable analogues of pyrophosphate that bind hydroxyapatite and are released inside osteoclasts, inhibiting bone resorption. Potency depends on the side chain, and a nitrogen atom greatly increases it.
Alendronate is the most commonly used. In postmenopausal women, 10 mg daily with calcium and vitamin D reduced vertebral fractures by about 50% and nonvertebral fractures by about 17%. 70 mg weekly gives equivalent BMD gains and is used in nearly all patients. It is poorly absorbed, so take it at least 30 minutes before food or other drugs, with at least 100 mL of water, and stay upright. It is also effective in glucocorticoid-induced osteoporosis and in men.
Zoledronic acid (IV) is effective, including in glucocorticoid-induced osteoporosis. The most common adverse effect is a self-limited acute-phase reaction (flu-like illness for 2 to 3 days after the first infusion, in 42% of women in the trial). Less common: hypocalcemia, atrial fibrillation and renal failure. Rare: jaw osteonecrosis and uveitis. Check renal function first and give only if eGFR is above 35 mL/min.
Risedronate (35 mg weekly) and ibandronate (50 mg monthly orally, or 3 mg IV every 3 months) are used less often.
Denosumab is a fully human monoclonal antibody against RANKL, 60 mg subcutaneously every 6 months. In postmenopausal osteoporosis it reduced vertebral fracture risk by about 68%, hip fracture by about 40% and nonvertebral fracture by about 20%. It is not renally cleared, so it can be used in renal failure, but ensure vitamin D and calcium adequacy to reduce hypocalcemia risk. Long-term treatment has been associated with rare jaw osteonecrosis and atypical femoral fractures. (Rockwood)
Teriparatide (PTH 1–34, 20 mcg daily subcutaneously) stimulates remodeling with a net anabolic effect, especially in trabecular bone such as the spine. Over 18 months in postmenopausal women it increased BMD and reduced vertebral fractures by about 65% and nonvertebral fractures by about 50%. It was superior to risedronate for vertebral fracture prevention in severe spinal osteoporosis, and superior to alendronate in glucocorticoid-induced osteoporosis. Side effects: headache, nausea, cramps, mild asymptomatic hypercalcemia. A boxed warning about osteosarcoma (from animal models) was based on rats, and 14-year surveillance found no difference from background incidence. Recommended duration is 2 years, followed by an antiresorptive to preserve the gain (raloxifene, alendronate and zoledronic acid have been effective).
Abaloparatide (PTHrP 1–34) acts like teriparatide, favoring bone formation over resorption, with a more transient cAMP activation. It reduced vertebral fractures versus placebo in postmenopausal women, and increased spine BMD by about 13% and total hip BMD by about 8%.
Romosozumab (sclerostin inhibitor): in the ARCH trial, 12 months of romosozumab followed by alendronate was significantly superior to alendronate alone for vertebral, nonvertebral, hip and clinical fractures. FRAME (versus denosumab) gave similar findings. It was more effective than teriparatide for spine and hip BMD in patients previously on alendronate. Serious cardiovascular events were more frequent with romosozumab in ARCH (2.5% vs 1.9%) but not in FRAME, and there is a boxed warning for myocardial infarction, stroke and cardiovascular death. It should not be used after prior MI or stroke.
Hormone replacement therapy prevents bone loss and fractures, but cardiovascular disease, venous thrombosis and breast cancer risk limit its use. (Rockwood)
Effects on Fracture Healing and Outcomes
Mortality after hip fracture surgery remains high: one-year mortality is about 30%. Within a cohort of over 115,000 patients aged over 65, the risk of a second hip fracture was 19% after any index fracture, and 33% after an index hip fracture, with a median 1.5 years to the second fracture. Zoledronic acid and denosumab after hip fracture were associated with lower all-cause mortality than no treatment (hazard ratios 0.70 and 0.64). (Rockwood)
Teriparatide is the most studied anabolic agent for fracture healing. In a randomized trial of 102 postmenopausal women with distal radius fractures treated with reduction and casting, radiographic union was faster (7.4 vs 9.1 weeks). In 224 surgically treated pertrochanteric fractures it improved pain scores versus risedronate. Despite anabolic benefits, there is no data to support its use as a fracture-healing adjuvant. Two randomized trials of romosozumab (surgical tibial shaft fractures, and intertrochanteric or femoral neck fractures in patients over 55) showed no benefit for union. (Rockwood)
Bisphosphonates and healing. Theoretically, suppressing resorption should delay healing, but experimental data do not confirm this. Alendronate 70 mg weekly started within 14 days of a distal radius fracture (n = 215 vs placebo, 206) caused no difference in radiographic union or function. In HORIZON, zoledronic acid given within 90 days of surgery for low-energy hip fracture (n = 1,065 vs placebo 1,062) showed no difference in healing across timing groups (less than 2 weeks, 2–4, 4–6, over 6 weeks). The American Society for Bone and Mineral Research task force concluded that bisphosphonates clearly prevent second fractures and can be started in hospital. (Rockwood)
Atypical Femoral Fractures (AFF)
Definition (ASBMR): typically four of five features: (1) minimal or no trauma; (2) origin in the lateral cortex with a mostly transverse pattern; (3) a medial spike in complete fractures, with incomplete fractures only lateral-based; (4) noncomminuted or minimally comminuted; (5) localized periosteal or endosteal thickening of the lateral cortex. (Rockwood)
Risk and benefit. In 10,000 White women treated for 3 years, there were 2 atypical fractures with 149 hip fractures and 541 clinical fractures prevented. At 5 years, the numbers were 8, 286 and 859. For Asian patients the 3-year profile was 8 AFFs against 91 prevented hip fractures. Asian ethnicity was independently associated with AFF risk after controlling for femoral geometry. (Rockwood)
Management (authors' preferred algorithm 4-1):
Stop antiresorptive therapy. If further osteoporosis treatment is needed, switch to an anabolic PTH analogue. Patients who have had an AFF have an equal or higher risk of later osteoporotic fractures than those with major osteoporotic fractures, so treatment should be considered.
Complete fracture: surgical treatment. Image the contralateral femur.
Incomplete AFF without pain: conservative care with weight-bearing restriction and bisphosphonate cessation can be considered.
Painful incomplete AFF: prophylactic fixation.
Stress reaction or radiolucent line: the author favors surgical fixation because of low healing rates with conservative care and a high rate of progression to complete fracture (one study: 55.8% vs 25.7%), regardless of pain.
Fixation: intramedullary nails, particularly piriformis-entry nails, to reduce varus malreduction and varus forces in subtrochanteric AFFs. Healing rates were not associated with teriparatide use. (Rockwood)
Complications of Treatment
Bisphosphonates: acute-phase reaction, hypocalcemia, atrial fibrillation, renal impairment, rare jaw osteonecrosis, uveitis and atypical femoral fractures. (Rockwood)
Denosumab: hypocalcemia, rare jaw osteonecrosis and atypical femoral fractures. (Rockwood)
Teriparatide: headache, nausea, cramps, mild hypercalcemia. (Rockwood)
Romosozumab: cardiovascular events (boxed warning). (Rockwood)
References
Chapter 4, osteoporosis and metabolic bone disease. In: Tornetta P III, Ricci WM, Ostrum RF, McKee MD, Ollivere BJ, de Ridder VA, eds. Rockwood and Green's Fractures in Adults. 10th ed. Wolters Kluwer; 2024 (Turkish edition: Erişkin Kırıkları).