Metabolic Bone Disease Flashcards
Osteoporosis definition
- a condition characterized by decreased bone mass and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility and suscepti-bility to fracture bone mineral density (BMD) ≥2.5 standard deviations below the peak bone mass for young adults (i.e. T-score ≤–2.5)
- osteopenia: BMD with T-score between –1.0 and –2.5
Osteoporosis etiology and pathophysiology
Primary Osteoporosis (95% of osteoporosis in women and 80% in men) • primary type 1: most common in post-menopausal women, due to decline in estrogen, worsens with age • primary type 2: occurs after age 75, seen in females and males at 2:1 ratio, possibly due to zinc deficiency
Secondary Osteoporosis
- gastrointestinal diseases ■ gastrectomy ■ malabsorption (e.g. celiac disease) ■ chronic liver disease
- bone marrow disorders ■ multiple myeloma ■ lymphoma ■ leukemia
- endocrinopathies ■ Cushing’s syndrome ■ hyperparathyroidism ■ hyperthyroidism ■ premature menopause ■ DM ■ hypogonadism
- malignancy ■ secondary to chemotherapy ■ myeloma
- drugs ■ corticosteroid therapy ■ phenytoin ■ chronic heparin therapy ■ androgen deprivation therapy ■ aromatase inhibitors
- other ■ rheumatologic disorders ◆ rheumatoid arthritis ◆ SLE ◆ ankylosing spondylitis ■ renal disease ■ poor nutrition ■ immobilization
- COPD (due to disease, tobacco, and glucocorticoid use)
Osteoporosis clinical features
- commonly asymptomatic
- height loss due to collapsed vertebrae
• fractures: most commonly in hip, vertebrae, humerus, and wrist
■ fragility fractures: fracture with fall from standing heght
■ Dowager’s hump: collapse fracture of vertebral bodies in mid-dorsal region
■ x-ray: vertebral compression and crush fractures, wedge fractures, “codfishing” sign (weakening of subchondral plates and expansion of intervertebral discs)
• pain, especially backache, associated with fractures
Osteoporosis approach
- assess risk factors for osteoporosis on history and physical
- decide if patient requires BMD testing with dual-energy x-ray absorptiometry (DEXA): men and women ≥65 yr or younger if presence of risk factors
- initial investigations
■ all patients with osteoporosis: calcium corrected for albumin, CBC, creatinine, ALP, TSH
■ also consider serum and urine protein electrophoresis, celiac workup, and 24 h urinary Ca2+ excretion to rule out additional secondary causes
■ 25-OH-Vitamin D level should only be measured after 3-4 mo of adequate supplementation and should not be repeated if an optimal level ≥75 nmol/L is achieved
■ lateral thoracic and lumbar x-ray if clinical evidence of vertebral fracture - assess 10-yr fracture risk by combining BMD result and risk factors (only if ≥50 yr)
1) WHO Fracture Risk Assessment Tool (FRAX)
2) Canadian Association of Radiologists and Osteoporosis Canada Risk Assessment Tool (CAROC)
◆ approach to management guided by 10-yr risk stratification into low, medium, high risk - for all patients being assessed for osteoporosis, encourage appropriate lifestyle changes
Indications for BMD testing
Older adults (age 50+ years):
All women and men age ≥65 yr
Menopausal women, and men aged 50-64 yr with clinical risk factors for fracture:
Fragility fracture after age 40
Prolonged glucocorticoid use
Other high-risk medication use (aromatase inhibitors, androgen deprivation therapy)
Parental hip fracture
Vertebral fracture or osteopenia identified on x-ray
Current smoking
High alcohol intake
Low body weight (<60 kg) or major weight loss (>10% of weight at age 25 yr)
Rheumatoid arthritis
Other disorders strongly associated with osteoporosis: primary hyperparathyroidism, type 1 DM, osteogenesis imperfecta, uncontrolled hyperthyroidism, hypogonadism or premature menopause (<45 yr), Cushing’s disease, chronic malnutrition or malabsorption, chronic liver disease, COPD and chronic inflammatory conditions (e.g. inflammatory bowel disease)
Younger adults (age <50 years): Fragility fracture: Prolonged use of glucocorticoids Use of other high-risk medications (aromatase inhibitors, androgen deprivation therapy, anticonvulsants) Hypogonadism or premature menopause Malabsorption syndrome Primary hyperparathyroidism Other disorders strongly associated with rapid bone loss and/or fracture
Osteoporosis risk stratification and next steps
Low Risk - 10 yr fracture risk <10%
Unlikely to benefit from pharmacotherapy; encourage lifestyle changes
Reassess risk in 5 yr
Medium Risk - 10 yr fracture risk 10-20%
Discuss patient preference for management and consider additional risk factors Factors that warrant consideration for pharmacological therapy:
Additional vertebral fracture(s) identified on vertebral fracture assessment (VFA) or lateral spine x-ray
Previous wrist fracture in individuals ≥65 or with T-score ≤–2.5
Lumbar spine T-score much lower than femoral neck T-score
Rapid bone loss
Men receiving androgen-deprivation therapy for prostate cancer
Women receiving aromatase-inhibitor therapy for breast cancer
Long-term or repeated systemic glucocorticoid use (oral or parenteral) that does not meet the conventional criteria for recent prolonged systemic glucocorticoid use
Recurrent falls (defined as falling 2 or more times in the past 12 mo)
Other disorders strongly associated with osteoporosis
Repeat BMD and reassess risk every 1-3 yr initially
High Risk - 10 yr fracture risk >20%; OR Prior fragility fracture of hip or spine; OR More than one fragility fracture
Start pharmacotherapy
Osteoporosis treatment
Treatment for both men and women
Lifestyle
Diet: Elemental calcium 1000-1200 mg/d; Vit D 1000 IU/d
Exercise: 3x30 min weight-bearing exercises/wk
Cessation of smoking, reduce caffeine intake
Stop/avoid osteoporosis-inducing medications
Drug therapy:
Bisphosphonate: inhibitors of osteoclast binding
1st line in prevention of hip, nonvertebral, and vertebral # (Grade A): alendronate, risedronate, zoledronic acid
2nd line (Grade B): etidronate
RANKL Inhibitors
Denosumab: 1st line in prevention of hip, nonvertebral, vertebral # (Grade A)
Parathyroid Hormone
YES fragility #: 18-24 mo duration
Calcitonin (2nd line) osteoclast receptor binding
YES fragility #: Calcitonin 200 IU nasally OD with Calcitriol 0.25 µg bid
Treatment specific to post-menopausal women:
SERM (selective estrogenreceptor modulator): agonistic effect on bone but antagonistic effect on uterus and breast
Raloxifene: 1st line in prevention of verteb al # (Grade A)
+ve: prevents osteoporotic # (Gr de A to B evidence), improves lipid profile, decreased breast ca risk
-ve: increased risk of DVT/PE, stroke mortality, hot flashes, leg cramps
HRT: combined estrogen + progesterone
1st line in prevention of hip, nonvertebral, and vertebral # (Grade A)
For most women, risks > benefits
Combined estrogen/progestin prevents hip, vertebral, total #
Increased risks of breast cancer, cardiovascular events, and DVT/PE
Clinical signs of fractures or osteoporosis
- Height loss >3 cm (Sn 92%)
- Weight <51 kg
- Kyphosis (Sp 92%)
- Tooth count <20 (Sp 92%)
- Grip strength
- Armspan-height difference >5 cm (Sp 76%)
- Wall-occiput distance >0 cm (Sp 87%)
- Rib-pelvis distance ≤2 finger breadth (Sn 88%)
Calcium Plus Vitamin D Supplementation and Risk of Fractures. Osteoporosis
Systematic analysis suggests that Vitamin D and Calcium therapy significantly decreases fracture risk. This study did not specifically look at individuals with osteoporosis. However, it still supports that Vitamin D and Calcium should continue to be used as preventative treatment for individuals at increased risk of fractures.
Calcium Plus Vitamin D Supplementation and Risk of Fractures. Osteoporosis
Systematic analysis suggests that Vitamin D and Calcium therapy significantly decreases fracture risk. This study did not specifically look at individuals with osteoporosis. However, it still supports that Vitamin D and Calcium should continue to be used as preventative treatment for individuals at increased risk of fractures.
What is considered a positive wall-occiput test for thoracic fracture
> 0 cm
What is considered a positive Rib-Pelvis distance test for Lumbar fracture
Rib-pelvis distance 0-2 fringerbreadths
What to ask before prescribing Calcitonin
Before prescribing Calcitonin, remember to ask about fish allergies
Rickets definition
osteopenia with disordered calcification leading to a higher proportion of osteoid (unmineralized) tissue prior to epiphyseal closure (in childhood)
Osteomalacia definition
osteopenia with disordered calcification leading to a higher proportion of osteoid (unmineralized) tissue after epiphyseal closure (in adulthood)
Factors necessary for mineralization
- Quantitatively and qualitatively normal osteoid formation
- Normal concentration of calcium and phosphate in ECF
- Adequate bioactivity of ALP
- Normal pH at site of calcification
- Absence of inhibitors of calcification
Osteomalacia and Rickets etiology and pathophysiology
Vitamin D Deficiency
• deficient uptake or absorption
■ nutritional deficiency
■ malabsorption: post-gastrectomy, small bowel disease (e.g. Celiac sprue), pancreatic insufficiency
• defective 25-hydroxylation
■ liver disease
■ anticonvulsant therapy (phenytoin, carbamazepine, phenobarbital)
• loss of vitamin D binding protein
■ nephrotic syndrome
• defec ive 1-α-25 hydroxylation
■ hypoparathyroidism
- renal failure
- pathophysiology: leads to secondary hyperparathyroidism and hypophosphatemia
MINERALIZATION DEFECT
• abnormal matrix
■ osteogenesis imperfecta
■ fibrogenesis imperfecta
■ axial osteomalacia
• enzyme deficiency
■ hypophosphatasia (inadequate ALP bioactivity)
• presence of calcification inhibitors
■ bisphosphonates, aluminum, high dose fluoride, anticonvulsants
Osteomalacia and Rickets clinical presentation
Rickets
Skeletal pain and deformities, bow legged Fracture susceptibility Weakness and hypotonia Disturbed growth Ricketic rosary (prominent costochondral junctions) Harrison’s groove (indentation of lower ribs) Hypocalcemia
Osteomalacia
Not as dramatic Diffuse skeletal pain Bone tenderness Fractures Gait disturbances (waddling) Proximal muscle weakness Hypotonia
Osteomalacia and Rickets investigations
Vitamin D deficiency Serum Phosphate - dec Serum calcium - dec to normal Serum ALP - inc Other features - dec calcitriol
Hypophosphatemia
Serum phosphate - dec
Serum calcium - normal
Serum ALP - dec to normal
Proximal RTA Serum phosphate - dec Serum Ca - normal Serum ALP - normal Other features - associated with hyperchloremic metabolic acidosis
Conditions associated with abnormal matrix formation
Serum phosphate - normal
Serum Ca - Normal
Serum ALP - normal
• radiologic findings
■ pseudofractures, fissures, narrow radiolucent lines – thought to be healed stress fractures or the result of erosion by arterial pulsation
■ loss of distinctness of vertebral body trabeculae; concavity of the vertebral bodies
■ changes due to secondary hyperparathyroidism: subperiosteal resorption of the phalanges, bone cysts, resorption of the distal ends of long bones
■ others: bowing of tibia, coxa profundus hip deformity
• bone biopsy: usually not necessary but considered the gold standard for diagnosis
Osteomalacia and Rickets treatment
- definitive treatment depends on the underlying cause
- vitamin D supplementation
- PO43- supplements if low serum PO43-, Ca2+ supplements for isolated calcium deficiency
- bicarbonate if chronic metabolic acidosis
KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease
Recommendations for Metabolic Bone Disease in CKD
Screening
- Regular bone mineral density screening of patients with eGFR<45 is not recommended
- No consensus regarding optimal intervals for screening PO43- and Ca2+ levels
- Screening Vitamin D and PTH is not recommended
Management
• Best fracture prevention strategy is fall risk assessment and fall prevention measures
• No clear evidence that manipulation of Ca2+, Vitamin D, PO43-, or PTH results in improved outcomes
Renal osteodystrophy definition and types and potential complications
• changes to mineral metabolism and bone structure secondary to chronic kidney disease
• represents a mixture of four types of bone disease:
■ osteomalacia: low bone turnover combined with increased unmineralized bone (osteoid)
■ adynamic bone disease: low bone turnover due to excessive suppression of parathyroid gland
■ osteitis fibrosa cystica: increased bone turnover due to secondary hyperparathyroidism
■ mixed uremic osteodystrophy: both high and low bone turnover, characterized by marrow fibrosis and increased osteoid
• metastatic calcification secondary to hyperphosphatemia may occur
Renal osteodystrophy pathophysiology
- metaboli bone disease secondary to chronic renal failur
* combnation of hyperphosphatemia (inhibits 1,25(OH)2-Vit D synthesis) and loss of renal mass (reduced 1-α-hydroxylase)
Renal osteodystrophy clinical features
• soft tissue calcifications, necrotic skin lesions if vessels involved • osteodystrophy, generalized bone pain and fractures • pruritu • neuromuscular irritability and tetany may occur • radiologic features of osteitis fibrosa cystica, osteomalacia, osteosclerosis, osteoporosis
