Pathophysiology of Bone, Calcium Homeostasis PDF

1 By the end of this unit, you will learn and understand: ¡ ¡ ¡ ¡ ¡ Pathophysiology of PTH excess or deficiency Pathophysiology of FGF-23, calcitonin Osteoporosis Osteomalacia Osteoarthritis 2 § Secreted by parathyroid glands § Increases Ca++ when serum levels are low § Highly responsive to alterati...

1 By the end of this unit, you will learn and understand: ¡ ¡ ¡ ¡ ¡ Pathophysiology of PTH excess or deficiency Pathophysiology of FGF-23, calcitonin Osteoporosis Osteomalacia Osteoarthritis 2 § Secreted by parathyroid glands § Increases Ca++ when serum levels are low § Highly responsive to alterations in serum calcium concentrations – changes within seconds ▪ Low serum Ca++ à Stimulate PTH secretion ▪ High serum Ca++ à suppresses PTH synthesis and secretion 3 ¡ PTH hypersecretion (hyperparathyroidism) § Because PTH increases [Ca++], hyperparathyroidism results in § § § § hypercalcemia. Primary disease (of the gland itself) usually caused by a hypersecreting tumor ▪ Parathyroid hyperplasia in 1 or more (up to 4) glands ▪ Can happen with multiple endocrine neoplasia (MEN) syndromes. Secondary disease due to a defect outside of the glands Long-term PTH and hypercalcemia can lead to kidney stones, low bone mass. Can be life-threatening due to longer-term or acute pathological effects of hypercalcemia (é Ca++ causes ê neuromuscular excitability and cardiac arrhythmias) 4 Parathyroid hormone-related peptide (PTHrP) § Occurs in 10% of all malignancies, especially solid tumors that can produce PTHrP (squamous cell carcinomas – e.g. lung, esophagus; renal; breast) and in 1/3 of multiple myeloma. § Leads to extreme illness including nausea, vomiting, dehydration, confusion, coma. § Binds to type 1 PTH receptor, which is mainly on bone and kidney. 5 § Results in hypocalcemia. § Very rare. Typically due to removal of, or trauma to, the parathyroid glands. ▪ During thyroid or parathyroid surgery, the blood supply to the parathyroid gland must be preserved. § Rare genetic or autoimmune disorders. § Symptoms and signs of hypocalcemia: ▪ Confusion, weakness, behavioral changes (mental retardation during development) ▪ Neuromuscular – seizures, spasms, muscle cramps ▪ Cardiac – rhythmicity, heart failure ▪ Ocular – cataracts ▪ Dental ▪ Respiratory 6 FGF-23 plays a central role in regulating phosphate homeostasis. (FGF-23 is stimulated when phosphate is high; its job is to restore serum phosphate to physiological levels) Pathophysiology: FGF-23 excess – hypophosphatemia Usually asymptomatic unless it is chronic or developmental Hypophosphatemic rickets (X-linked or autosomal) Tumor-induced osteomalacia (defect in bone mineralization). Muscle weakness, bone pain, increased cardiac events Loss of FGF-23 function leads to hyperphosphatemia Muscle cramps, numbness, bone and joint pain 7 Calcitonin’s main function is to lower serum Ca++ Pathophysiology: § Because calcitonin is secondary to PTH in its actions, loss of calcitonin is not treated ▪ If the thyroid is removed, thyroid hormone must be replaced, but calcitonin is not. § Medullary carcinoma of the thyroid – a C-cell neoplasm, accounting for 5-10% of thyroid malignancies. § Common in patients with multiple endocrine neoplasia syndrome 2 (MEN-2) 8 Osteopenia: lower-than-normal bone mass or density, less severe than osteoporosis Bone mass in women – importance of age and nutrition/exercise § Gonadal steroid hormones, especially estradiol ▪ Women – Estrogen deficiency at menopause. ▪ Men – Testosterone plays some of the same roles as estrogens in women, but estradiol (from peripheral aromatization of testosterone) is the key hormone for development and preservation of bone mass in men. ▪ Hypogonadal men – accelerated bone loss ▪ Men on androgen deprivation therapy for prostate cancer – increased risk for bone loss and fracture. § Adrenal steroids (glucocorticoids) ▪ See next slide 11 § Natural or pharmaceutical corticosteroids – reduced bone formation rates in chronic glucocorticoid therapy, or Cushing’s syndrome (cortisol excess) § Other medications ▪ ▪ ▪ ▪ Excessive thyroid hormone Anticonvulsants Chronic heparin therapy Alcohol, smoking § Inadequate diet – intake of calcium, vitamin D. § Load-bearing exercise is protective against osteoporosis 12 § Bone loss can result from increased bone resorption, decreased bone formation, or a combination. ▪ Young adults with low bone mass typically have low bone formation/accrual. ▪ Postmenopausal osteoporosis is due to accelerated bone resorption. Typically, there is an imbalance such that osteoblastic activity cannot keep pace with bone resorption by osteoclasts. 13 § Trabecular bone is most vulnerable, as it is remodeled more rapidly. § 5-10% of spinal trabecular bone mineral is lost per year in early postmenopausal women. ▪ Osteoporotic fractures can occur in spine. § After 5-15 years, the rate of bone loss slows. ▪ After age 65, rate of bone loss is similar in the sexes. 14 § Relative deficiency of calcium and 1,25(OH)2-D3. § Capacity of the intestine to absorb calcium diminishes with age. § Dietary calcium intake must be increased. 15 Asymptomatic until fractures and deformity occur. Fractures typically happen in spine, hip, wrist (Colles fracture). Vertebral bodies may be crushed, causing loss of height. If vertebral bodies are wedged anteriorly, this results in height loss, kyphosis. Dorsal kyphosis results from anterior wedging of multiple thoracic vertebrae. 16 Greatest association with morbidity and mortality. Sharply rising incidence after 80 yrs of age Complications: pulmonary embolus, pneumonia ~half of elderly people never walk freely again. 18 X-ray is poor diagnostic tool – misses 30-50% of spinal osteoporosis. Dual-energy x-ray absorptiometry (DXA) is gold standard. Cut-off from WHO is bone mineral density (BMD) value 2.5 standard deviations or more below low adult normal value; T-score < -2.5. Other risk factors should be included such as age, propensity for falls. Absolute 10-yr fracture risk calculation algorithm, “FRAX,” incorporates femoral neck BMD and other clinical risk factors. www.shef.ac.uk/FRAX/ 19 Total calcium intake 1200-1500 mg/d. Vit D 600-800 IU/d (see slide 15) Postmenopausal women: Estrogen replacement (with progesterone for women with uterus; and considering risk/benefits). 20 Defect in mineralization of bone. In young individuals, it affects growth plate – rickets – bowed legs due to soft bones and unmineralized cartilage that bends under the child’s weight. Associated with bone pain, muscle weakness, waddling gait. Reduced bone mass. Characterized by “pseudofracture” – local bone resorption. 21 ¡ ¡ ¡ ¡ ¡ Vitamin D deficiency can happen through decreased sunlight/increased sunscreens and limited dietary intake. Malabsorption of Vit D Genetic disorders Phosphate deficiency, usually due to renal problems. Tumors overproducing FGF-23 22 https://www.hopkinsarthritis.org/arthritisinfo/osteoarthritis/oa-pathophysiology/ ¡ ¡ ¡ ¡ ¡ OA is the most common type of arthritis. X-rays are adequate for diagnosis. MRI is sometimes used for complex cases. Defined by radiographic criteria, symptoms, or both. Most common in distal and proximal interphalangeal joints of the hand (may be asymptomatic) Knee and hip are usually symptomatic. 23 ¡ Risk factors: § Age § Sex (female) § Obesity § Joint stress (e.g. occupation related repetitive injury and physical trauma) § Genetics 24 ¡ ¡ ¡ ¡ Joint pain that worsens with activity and relieved by rest. Bony enlargements, crepitus (grating sound), tenderness on palpation. Radiographic findings: osteophyte (bony outgrowth) formation, joint space narrowing, subchondral sclerosis (layer of bone beneath the cartilage), cysts. Typically diagnosed by x-ray, more recently by MRI that provides information on cartilage. 25 ¡ Disease of cartilage § Cartilage is composed mainly of type II collagen and proteoglycans. ¡ ¡ ¡ Normal cartilage cells are subjected to dynamic remodeling that maintains cartilage volume. Inflammatory changes – increases in pro-inflammatory cytokines, over-expression of matrix degrading enzymes Treated with acetaminophen, NSAIDs. 26 By the end of this unit, you will learn and understand: ¡ ¡ ¡ ¡ ¡ Pathophysiology of PTH excess or deficiency Pathophysiology of FGF-23, calcitonin Osteoporosis Osteomalacia Osteoarthritis 27