In osteomalacia; the mineralization rate of the bone is reduced, the bone mass is preserved.
In osteoporosis; the mineralization rate of the bone is preserved, the bone mass decreases.
• The most important complication of osteoporosis is bone fractures. Osteoporotic bone fractures are associated with increased morbidity and mortality.
Risk factors for osteoporotic fractures
unmodifiable
History of fracture in adulthood
Fracture history in first degree relative
female gender
advanced age
The white race
dementia
modifiable
Active smoking
Estrogen deficiency
o Early menopause (< 45 years old)
o Bilateral oophorectomy
o Prolonged premenstrual amenorrhea (>1 year)
Low calcium and vitamin D intake
Alcoholism
visual disturbances
repetitive falls
insufficient physical activity
Poor state of health (frailty)
Clinic
• Osteoporosis is usually asymptomatic until fracture develops.
• Pain develops as a result of osteoporotic fracture. (It should be noted that vertebral fractures in particular may be silent)
• Shortening in stature, kyphosis, restrictive lung disease, inability to walk/immobilization, deep vein thrombosis, etc. may develop.
pathophysiology
• Bone remodeling
o RANK ligand (RANKL);
■ It is secreted from osteocytes and osteoblasts.
■ Its receptor is RANK (on the osteoclast).
■ RANK-RANKL association stimulates osteoclast development and activation.
o Osteoprotegerin (OPG)
■ It is RANKL's trapping pseudo-receptor (inhibits RANK-RANKL interaction)
■ It is secreted from osteocytes and osteoblasts.
o Wnt signaling pathway
■ By increasing osteoblast, activity and production, bone formation is increased
RANKL secretion is reduced, osteoclast production and activity are reduced.
o Sclerostin;
■ Produced by osteocytes.
■ Major inhibitor of Wnt trough.
• Balance between bone resorption and new bone formation;
o Bone formation overtakes bone resorption in young adults. Maximum bone mass is reached at 30-40 years of age. After these ages, bone destruction exceeds new bone formation.
• Dietary calcium and vitamin D intake
o Insufficient calcium and vitamin D intake causes secondary hyperparathyroidism and is an important risk factor for osteoporosis and fracture development.
• Estrogen status
o In estrogen deficiency; RANKL production increases, osteoprotegerin production decreases, osteoclast formation and activity increase.
o Trabecular bone is primarily affected in estrogen deficiency
o Fractures are seen in the vertebrae at the earliest (Trabecular bone is the most in the vertebrae)
• Physical activity
o Prolonged bed rest or immobilization due to paralysis leads to bone loss.
• Cigaret
o It is toxic to osteoblasts and acts indirectly by changing estrogen metabolism
Some protective factors from osteoporosis
Obesity
Exercise
Thiazide diuretic
Primary causes of osteoporosis
Aging
menopause
secondary causes of osteoporosis
hypogonadism
Turner syndrome
Klinefelter syndrome
anorexia nervosa
hypothalamic amenorrhea
hyperprolactinemia
endocrine disorders
mCushing's syndrome
hyperparathyroidism
thyrotoxicosis
Diabetes mellitus (Types 1 and 2)
acromegaly
adrenal insufficiency
Nutritional and gastrointestinal system disorders
malnutrition
parenteral nutrition
Malabsorption syndromes
gastrectomy
Serious liver diseases (especially primary biliary cirrhosis)
rheumatological disorders
rheumatoid arthritis
Ankylosing spondylitis
medicines
glucocorticoid
cyclosporine and tacrolimus
cytotoxic drugs
Anticonvulsants
Aromatase inhibitors
Selective serotonin reuptake inhibitors (SSRIs)
excess thyroxine
Aluminum
GnRH agonists
heparin
Lithium
proton pump inhibitors
Thiazolidinediones
canagliflozin
Antiandrogen drugs
Hematological disorders/ malignancy
multiple myeloma
leukemia and lymphoma
Malignant that produces PTH-related peptide
tumors
mastocytosis
Hemophilia
thalassemia
hereditary disorders
Osteogenesis imperfecta
Marf an syndrome
hemochromatosis
hypophosphatasia
Glycogen storage diseases
homocystinuria
Ehler Danlos syndrome
porphyria
Menkes syndrome
Gaucher's disease
Epidermolysis bullosa
diagnosis
• DXA (Dual Energy X-Ray Absorbtiometry)
o It is used in the measurement of bone density. The measurement is often made from the hip and lumbar vertebrae.
o DXA results are evaluated by T-score (Patients are compared with younger same-sex population).
o T score:
> -1.0 Normal bone mass
Between -1.0 and -2.5 Osteopenia
<= -2.5 Osteoporosis
<= -2.5 + Fracture Severe osteoporosis
o In the Z score, patients are compared with the same population in terms of gender and age.
bone mineral density measurement indications
Female >= 65 years, male <= 70 years (regardless of risk factors)
Young postmenopausal, perimenopausal women and men aged 50-69 years (if risk factors are present)
People with fractures at age 50
Patients with a condition associated with low bone mass and increased bone loss or use of drugs (rheumatoid arthritis, steroid use, etc.)
• The absolute fracture risk assessment tool (FRAX) has been developed, as half of bone fractures occur with BMD values with a T score better than -2.5.
The parameters evaluated while calculating the FRAX score;
Age
Smoking
Gender
steroid use
Size
Presence of rheumatoid arthritis
Body weight
Cause(s) of secondary osteoporosis
Fracture history
Alcohol use
Parental history of hip fracture
Femoral neck BMD T score
• The FRAX score is used to predict fracture risk over the next 10 years.
• FRAX Patients with a 10-year risk of major fracture > 20% and hip fracture risk > 3% should receive osteoporosis treatment.
Laboratory evaluation of the osteoporotic patient
All osteoporosis/osteopenia patients
Serum creatinine, calcium, total protein, albumin, phosphorus, alkaline phosphatase, liver function tests
complete blood count
TSH
Calcium and creatinine in 24-hour urine
Serum 25(OH) vitamin D
If clinically indicated
Serum and urine protein electrophoresis (if total protein/albumin ratio > 2)
PTH
24-hour urine cortisol
Antigliadin and anti-endomysial antibodies
Morning fasting testosterone level
OSTEOPOROSIS TREATMENT
Nutritional recommendations
• Adequate calcium and vitamin D support should be provided to the patients.
Adequate calcium intake
Men and women (19-50 years) 1000 mg/day
Men and women (50-70 years) 1200 mg/day
Men and women (> 70 years) 1200 mg/day
Adequate vitamin D intake
Men and women (19-50 years) 200IU/day
Men and women (50-70 years) 400IU/day
Men and women (> 70 years) 600IU/day
• Daily vitamin D 1000-2000 IU can be given to patients with osteoporosis or high risk.
Exercise
• Weight-bearing exercises slow bone loss but do not provide new bone mass gain.
• It is also beneficial on neuromuscular function, reduces the risk of falling.
Pharmacological treatment of osteoporosis
• Who should be treated?
o Patients with fragility fractures of the hip and vertebra
o Patients with BMD T-score:S -2.5
o According to the FRAX score; patients with major fracture risk > 20%, hip fracture risk > 3%
drugs used to treat osteoporosis
Antiresorptive effects
Estrogen
raloxifene
Basodoxifen + Estrogen
Calcitonin
bisphosphonates
Denosumab
Anabolic effects
Estrogen
Abaloparatide
Mixing effects
Romosozumab
estrogens
• Estrogens can directly inhibit osteoclasts.
• A reduction in osteoporotic fractures is achieved in women receiving estrogen replacement.
Selective estrogen receptor modulators (SERM)
• Raloxifene
o Approved for the prevention and treatment of osteoporosis in postmenopausal women.
o It reduces the risk of developing breast cancer (like tamoxifen).
o Does not increase the risk of developing uterine cancer (unlike tamoxifen).
o It increases the risk of deep vein thrombosis and symptoms of hot flashes.
• Bazodoxifen; It is used with conjugated estrogen.
Bisphosphonates (Alendronate, Risedronate, Ibandronate, Zoledronate)
• Bisphosphonates are pyrophosphate analogs and bind to hydroxyapatite crystals by penetrating into the bone matrix.
• They specifically impair osteoclast function and reduce the number of osteoclasts (by inducing apoptosis).
• Bisphosphonate side effects
o All bisphosphonates can cause musculoskeletal and joint pain.
o After IV zoledronate infusion, acute phase reaction symptoms (fever, myalgia, headache, malaise, etc.) occur.
o All oral bisphosphonates can cause esophageal irritation and esophagitis.
It is contraindicated in patients with insufficient esophageal emptying and in the presence of strictures.
The drug should be taken with plenty of water and should be kept in an upright posture until half an hour after taking the drug.
o Potential for renal toxicity (GFR < 30-35 ml/min contraindicated)
o Hypocalcemia may develop.
o Osteonecrosis of the jaw
o Atypical femur fracture (> 5 years of use)
Calcitonin
• Calcitonin blocks osteoclast activity by binding directly to its receptor on osteoclast.
• It has analgesic effect.
• Associated with an overall increased risk of cancer.
Denosumab
• It is a monoclonal antibody developed against RANK Ligand.
• It has an inhibitory effect on osteoclast development and activity.
• Similar to bisphosphonates, it can cause osteonecrosis of the jaw and atypical femur fracture.
Teriparatide
• It is a PTH analog.
• It is used in patients with painful vertebral osteoporotic fractures.
• Teriparatide has a direct effect on osteoblast activity (anabolic effect).
• May cause hypercalcemia.
• It increases the risk of developing osteosarcoma. Therefore;
o The maximum treatment period is limited to 2 years.
o It is contraindicated in cases that increase the risk of developing osteosarcoma (Paget's disease, radiotherapy, etc.).
Abaloparatide
• synthetic analog of human PTH-related peptide (PTHrP).
• Compared to teriparatide; similar stimulation of bone formation, less bone resorption.
Romosozumab
• It is a monoclonal antibody developed against sclerostin.
• It creates an increase in bone formation and a decrease in its destruction.
Odanacatib
• It is a cathepsin K inhibitor, it prevents bone resorption by osteoclasts.
• Its production has been stopped because it increases the risk of stroke.
strontium ranelate
• It is essentially antiresorbtive.
• Increases bone mineral density (possibly related to its own accumulation)