Biology, Genetics & Bone Healing MCQs

Rickets is a disorder of bones in children that results from decreased calcium available in the blood resulting in poor mineralization of bone that can lead to fractures and deformity. The most common cause of rickets is from vitamin D deficiency but it can also be caused by poor nutrition or gastrointestinal disease that results in poor calcium absorption such as celiac disease or severe diarrhea from other causes. Rickets is not primarily a physeal disorder. Osteogenesis imperfecta is caused by a defect in type I collagen. A defect in the ext-1 gene is often seen in patients with multiple hereditary exostoses. Fibrous dysplasia also can result in bone deformity and fractures due to production of dysplastic fibrous bone but is not caused by calcium or vitamin D deficiency.

Trabecular bone is remodeled through osteoclast activation that creates a resorption pit known as a Howship lacuna. After the pit is formed, osteoclasts are replaced by osteoblasts that form new bone matrix. The cement line separates new bone formation from resorption. Cutting cones are created in cortical bone remodeling. Haversian canals carry nerves and blood vessels longitudinally in bone, while Volkmann canals connect different Haversian canals.

OPG is a receptor that competitively binds with RANKL, blocking the interaction with RANK and inhibiting osteoclastogenesis. PTH, secreted by the chief cells of the parathyroid gland, is active in calcium homeostasis independent of inflammatory arthropathies. PTH increases serum calcium indirectly by binding to osteoblasts, increasing expression of RANKL and decreasing expression of OPG. The interaction of RANKL to RANK in turn stimulates osteoclast precursors to fuse, formingosteoclasts to enhance bone resorption. The pannus of rheumatoid arthritis and monosodium urate crystals of gouty tophi have been shown to trigger release of inflammatory cytokines such as IL-6, IL-8 and tumor necrosis factor alpha. The key to osteoclastic bone resorption of inflammatory arthropathy is regulated by the interaction of RANKL, expressed in osteoblasts and activated T cells, and RANK, expressed in osteoclast progenitors and mature osteoclasts. In inflammatory arthropathy, RANKL expression is increased and OPG is reduced, resulting in increased cortical and subchondral bone.

The patient has transient osteoporosis of the hip. Transient osteoporosis is usually a self-limited condition that is most frequently seen in women in the third trimester of pregnancy and in men in the sixth decade of life. Transient osteoporosis is best treated with protected weight bearing.

Members of the Transforming Growth Factor-beta (TGF-β) superfamily, particularly TGF-β1, TGF-β3, and certain Bone Morphogenetic Proteins (BMPs), are the primary chondroinductive factors used in vitro and in tissue engineering to drive undifferentiated mesenchymal stem cells toward a chondrogenic lineage.

SOX9 is the master regulatory transcription factor for chondrogenesis. It directly binds to and activates enhancer elements of key cartilage matrix genes, including COL2A1 (Type II collagen) and ACAN (aggrecan). RUNX2 and Osterix are key regulators of osteogenesis. Scleraxis is associated with tenogenesis/ligamentogenesis.

Passage of sodium through a voltage-gated channel will lead to generation of a nerve action potential.Voltage-gated channel are shut when the membrane potential is near the resting potential of the cell, but they rapidly begin to open if the membrane potential increases to a precisely defined threshold value. When the channels open (in response to depolarization in transmembrane voltage), they allow an inward flow of sodium ions, which changes the electrochemical gradient, which in turn produces a further rise in the membrane potential. This then causes more channels to open, producing a greater electric current across the cell membrane, and so on.Lee et al. present a review article on nerve conduction and needle electromyography studies. They note that the three types of nerve conduction study are motor, sensory,and mixed, of which motor is the least sensitive. In addition, they report that peripheral nerve entrapment initially results in focal demyelination; thus, nerve conduction velocity slows across the site. However, with radiculopathy and nerve root compression, the nerve conduction study may be normal.Catterall presents a review article covering an overview of structural models of voltage-dependent activation, sodium selectivity and conductance, drug block and both fast and slow inactivation. He notes that voltage-gated sodium channels initiate action potentials in nerve, muscle and other excitable cells.Illustration A is a diagram that shows the electrical recordings of an action potential, along with labels of each section of the process.

DISCUSSION: Intramembranous ossification occurs through the direct formation of bone without the formation of a cartilaginous intermediate. Clinically, both intramembranous and endochondral ossification occur simultaneously during fracture healing; however, the latter is characterized by the differentiation and maturation of chondrocytes, vascular invasion of a hypertrophic cartilage matrix, and bone formation. Collagens type II and X are cartilage specific and would be characteristic of endochondral ossification, not intramembranous ossification.

Mesenchymal stem cells are pluripotent cells that can differentiate into many lineages including osteoblasts, adipocytes, myoblasts, chondroblasts, and fibroblasts. Runx2 and Osx appear to be required for differentiation to osteoblastic lines. PPARy2 andC/EBPa are transcription factors leading to adipocytes, MyoD promotes myoblasts, and Sox 9 corresponds to chondroblasts.

Spontaneous osteonecrosis of the medial femoral condyle is seen in the MRI scans, and is most common in women older than age 60 years. Although usually present in the weight-bearing portion of the medial femoral condyle, spontaneous osteonecrosis has also been described involving the lateral femoral condyle and patella. Most patients are seen postcollapse, and the treatment of choice is arthroplasty. Optimal treatment in precollapse stages is controversial.

In long bones, radiographs initially show a radiolucency in the metaphysis that progresses into the diaphysis. The entire progression of the disease takes years.The radiograph here shows the typical Paget’s lesion in the right iliac wing with mixed lytic and sclerotic areas.

A DEXA scan is most appropriately used to establish a baseline score. Even if the bone mineral density is not within the osteoporotic range (T-score less than -2.5), a prior fragility fracture is a strong risk factor for a second fracture. The guidelines of the National Osteoporosis Foundation indicate that, following a fragility hip fracture, active anti-osteoporotic medication should be initiated, whether or not a DEXA scan is performed.

DISCUSSION: Cell activation and transcription varies with the target cell, the growth factor-receptor combination, and the biologic state of the cell. The growth factors in the transforming growth factor-beta (TGF-β) superfamily signal through serine/threonine kinase receptors. Fibroblast growth factors, insulin-like growth factors, and platelet-derived growth factors signal through tyrosine kinase receptors. Growth hormone is released by the pituitary and circulates to the liver where target cells are stimulated to release insulin-like growth factor. REFERENCES: Lieberman J, Daluiski A, Einhorn TA: The role of growth factors in the repair of bone: Biology and clinical applications. J Bone Joint Surg Am 2002;84:1032-1044. Schmitt JM, Hwang K, Winn SR, et al: Bone morphogenetic proteins: An update on basic biology and clinical relevance. J Orthop Res 1999;17:269-278.

24,25-dihydroxycholecalciferol in an inactive form of Vitamin D. High levels of 1,25-dihydroxyvitamin D stimulate the enzymatic production of 24,25-dihydroxyvitamin D, the inactive form of vitamin D, thereby self-regulating the action of 1,25-dihydroxyvitamin D.Vitamin D is paramount to proper calcium homeostasis and has important clinical implications in the orthopaedic patient. Vitamin D3 is synthesized in the skin and is converted to 25-hydroxycholecalciferol in the liver. 25-hydroxycholecalciferol is then converted in the kidney into 1,25-dihydroxycholecalciferol, the active form of vitaminD. The best test to determine Vitamin D deficiency is the measurement of 25-hydroxycholecalciferol, as it has a longer half-life and circulating levels are 1,000x more than 1,25-dihydrocholecalciferol.Patton et al. review the importance of Vitamin D in the orthopaedic patient. They discuss the implications of Vitamin D deficiency, and urge orthopaedic surgeons to be proficient in both the diagnosis and treatment of the condition.Bogunovic et al. measured the levels of 25-hydroxycholecalciferol in 723 patients who were to undergo orthopaedic surgery. 40% of these patients were noted to be deficient in Vitamin D, with the highest rates in patients scheduled to undergo trauma and sports surgery.Illustration A reviews Vitamin D metabolism. 24,25-dihydroxycholecalciferol is referred to as pre-Vitamin D.Incorrect Answers:

DISCUSSION: There is a negative change of calcium balance with a decrease in intestinal absorption and an increase in urinary calcium loss. The reduction of intestinal absorption is accompanied by reduced circulating concentrations of total, but not free 1,25-dihydroxyvitamin D. However, estrogen may also directly regulate intestinal calcium resorption independent of vitamin D. Tubular resorption of calcium is higher in the presence of estrogen. Studies of the levels of PTH in the presence of estrogen are controversial. REFERENCES: Oh KW, Rhee EJ, Lee WY, et al: The relationship between circulating osteoprotegerin levels and bone mineral metabolism in healthy women. Clin Endocrinol (Oxf) 2004;61:244-249. Reid IR: Menopause, in Favus MJ (ed): Primer on Metabolic Bone Diseases and Disorders of Mineral Metabolism, ed 4. Philadelphia, PA, Lippincott Williams & Wilkins, 1999, pp 55-57.

The current recommendations for further prevention of any fragility fracture include 1200-1500mg of elemental calcium intake per day and 400-800 IU of vitamin D per day. Of note, these doses are indicated only for prevention and not sufficient for active treatment of osteoporosis (T score less than -2.5).Medications that are approved by the FDA for active treatment of osteoporosis: alendronate, risedronate, raloxifene, estrogen, calcitonin. These medications and preventative measures help to reduce fragility fractures by as much as 50%.Freedman et al. performed a retrospective study that looked at a cohort of patients with fragility fractures and then looked at the type and frequency of osteoporosis related interventions. They found that only 60% of patients actually were either prescribed a medication, given a referral, or ordered additional workup (DEXA scan).Schulman et al. reviewed a series of 80 female patients regarding osteoporosis and bone health, and found that the outpatient sports medicine office setting was an excellent opportunity to educate patients on these topics. The patients' post-education test scores increased significantly after a brief counseling session, and increases in daily calcium intake and exercise levels were also seen.

Transient osteoporosis of the hip is an uncommon problem, usually affecting women in the last trimester of pregnancy and middle-aged men. Symptoms include pain in the involved hip with temporary osteopenia; however, there is no joint space involvement. In this patient, the imaging findings are consistent with transient osteoporosis. Short TR/TE (repetition time/echo time) images reveal diffusely decreased signal intensity in the femoral head and intracapsular region of the femoral neck. Increased signal intensity is seen with increased T2-weighting. Within a few months, the pain, as well as the imaging findings, will completely resolve without intervention. Distinguishing the diffuse features of transient osteoporosis of the hip from the segmental findings of osteonecrosis is essential. Unlike transient osteoporosis of the hip, osteonecrosis will have a double-density signal on MRI and may progress radiographically. Surgical intervention and oral corticosteroids are not indicated for treatment. Protected weight bearing until the pain resolves may decrease symptoms while the transient osteoporosis resolves.

In osteopenia, elevated parathyroid hormone (PTH), high alkaline phosphatase as well as low calcium (Ca), phosphorus and vitamin D would be expected.In the setting of osteopenia/osteoporosis, there is a positive feedback to increase PTH in response to low serum calcium levels. In response, there is a corresponding increase in alkaline phosphatase and decrease in phosphorous and circulating vitamin D levels.Fraser writes a concise, yet thorough synopsis on primary and secondary hyperparathyroidism. In the article, the summary regarding osteopenia/osteoporosis (typically a state of hypovitamin D) begins by stating an initial state of decreased ionised calcium, which increases PTH, results in 3 primary effects: an attempt to increase gut absorption of Ca, mobilize Ca from the bone via osteoclasts and activate vitamin D at the kidney (1,25-vitamin D).Figure A exhibits a left femoral neck fracture, which is a fragility fracture associated with poor bone density. Illustration A is a figure from Fraser's article exhibiting the feedback loop from the hypothalamus, pituitary, adrenal/glandular axis.Incorrect answers:

Radiographic fusion success rates are best described as slightly rather than substantially improved. Hospital stay and time to fusion also are not substantially decreased. Use of BMP does eliminate the need for autograft harvest for anterior lumbar interbody fusion/cage. The need for postoperative bracing is not altered based on graft choice. Early studies of posterolateral fusion applications appear to show a greater potential benefit of rhBMP-2 over autograft.