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Biology, Genetics & Bone Healing MCQs

Practice Set 34 of 212

This practice set contains high-yield board review questions covering key concepts in Biology, Genetics & Bone Healing. Each clinical scenario is designed to test your diagnostic and management skills relevant to this subspecialty.

Question 661

Topic: Biology, Genetics & Bone Healing

A 74-year-old man reports progressive left hip pain with weight-bearing activities. A radiograph is shown in Figure 30. What is the most likely underlying diagnosis?

Anatomy Board Review 2008: High-Yield MCQs (Set 2) - Figure 39

. Infection
. Lymphoma
. Paget's disease
. Massive bone infarct
. Old pelvic trauma

Correct Answer & Explanation

. Paget's disease

Explanation

The radiograph shows enlargement of the bone, coarse trabeculation, a blastic appearance, and thickening of the cortex, revealing the classic appearance of Paget's disease in the sclerotic phase, the most common presentation. While lymphoma may present as a blastic lesion, it will not have the same enlargement, coarse trabeculation of bone, and the significant sclerosis seen here. Menendez LR (ed): Orthopaedic Knowledge Update: Musculoskeletal Tumors. Rosemont, IL, American Academy of Orthopaedic Surgeons, 2002, pp 211-215.

Question 662

Topic: Biology, Genetics & Bone Healing

Figures 45a and 45b show the AP and lateral radiographs of a 15-year old patient who is undergoing surgery to add 3 cm of length to the femur. Based on the radiographic findings, what is the next most appropriate step in management?

. The distraction rate should be maintained.
. The distraction rate should be decreased.
. The distraction should be reversed.
. The distraction gap should be managed with bone grafting in an open procedure.
. A repeat corticotomy should be performed.

Correct Answer & Explanation

. The distraction rate should be decreased.

Explanation

Because the radiographs reveal poor regenerate bone, especially anteriorly and laterally, the first step in management is to slow the distraction rate. If this does not solve the problem, temporary reversal of the distraction, or "accordionization," can be used to induce a greater healing response. Maintaining the same distraction rate will further impair regenerate formation and delay healing. Bone grafting should be reserved as an option if decreasing the distraction rate or alternating a week of compression with a week of distraction fails to improve the callus formation. Repeat corticotomy is performed in patients with premature consolidation. Raney EM: Limb-length discrepancy, in Fitzgerald RH, Kaufer H, Malkani AL (eds): Orthopaedics. St Louis, MO, Mosby, 2002, pp 1519-1526.

Question 663

Topic: Biology, Genetics & Bone Healing

Figure 49 shows the radiograph of a 3-year-old child with progressive bowlegs. Laboratory studies show a calcium level of 9.5 mg/dL (normal 9.0 to 11.0 mg/dL), a phosphorus level of 4.2 mg/dL (normal 3 to 5.7 mg/dL), and an alkaline phosphatase level of 305 IU/L (normal 104 to 345 IU/L). What is the most likely diagnosis?

Pediatrics Board Review 2001: High-Yield MCQs (Set 4) - Figure 6

. Blount's disease
. Hypophosphatemic rickets
. Nutritional rickets
. Schmid metaphyseal dysostosis
. Jansen metaphyseal dysostosis

Correct Answer & Explanation

. Schmid metaphyseal dysostosis

Explanation

The patient has bowlegs associated with very wide physes, particularly noted at the hips. The widening of the growth plates is a classic sign of rickets; however, the normal levels of calcium, phosphorus, and alkaline phosphatase rule out both nutritional and hypophosphatemic rickets. Patients with nutritional rickets or hypophosphatemic rickets have hypophosphatemia and increased alkaline phosphatase levels. Jansen metaphyseal dysostosis has very severe radiographic findings that are not found in this patient; however, these radiographic findings are classic for Schmid metaphyseal dysostosis. This disorder is caused by a mutation in the gene for type X collagen, which is found only in the growth plates of growing children. Lachman RS, Rimoin DL, Spranger J: Metaphyseal chondrodysplasia - Schmid type: Clinical and radiographic delineation with a review of the literature. Pediatr Radiol 1988;18:93-102.

Question 664

Topic: Biology, Genetics & Bone Healing

Osteoclasts are primarily responsible for bone resorption of malignancy. Which of the following stimulates osteoclast formation?

. RANKL gene (NF-kB ligand)
. Osteoprotegerin (OPG)
. Interleukin-5 (IL-5)
. Matrix metalloproteinase-2 (MMP-2)
. Collagen type I

Correct Answer & Explanation

. RANKL gene (NF-kB ligand)

Explanation

Bone destruction is primarily mediated by osteoclastic bone resorption, and cancer cells stimulate the formation and activation of osteoclasts next to metastatic foci. Increasing evidence suggests that receptor activator of NF-kB ligand (RANKL) is the ultimate extracellular mediator that stimulates osteoclast differentiation into mature osteoclasts. In contrast, OPG inhibits osteoclast development. IL-8 but not IL-5 is known to play a role in osteoclastogenesis. MMP-2 and collagen type I do not have a direct role in osteoclastogenesis. Kitazawa S, Kitazawa R: RANK ligand is a prerequisite for cancer-associated osteolytic lesions. J Pathol 2002;198:228-236.

Question 665

Topic: Biology, Genetics & Bone Healing

Figures 28a and 28b show the radiographs of a 79-year-old man who has constant knee pain. Prior to performing elective knee replacement surgery, management should include

. reduction of the serum alkaline phosphatase level by 50%.
. preoperative radiation therapy of 600 cGy to the surgical site.
. aspiration of the knee joint with cell count.
. insertion of a vena caval filter.
. administration of 25 mg of indomethacin three times a day.

Correct Answer & Explanation

. reduction of the serum alkaline phosphatase level by 50%.

Explanation

The radiographs show established Paget's disease. Bony expansion is evident, with thickened trabeculae consistent with the disordered bone remodeling process. A reduction of the serum alkaline phosphatase level to 50% of the pretreatment level may reduce pain from Paget's disease, and it is recommended prior to consideration of joint replacement. In elective cases, treatment of Paget's disease should begin at least 6 weeks prior to surgery. The other modalities are not related to the treatment of Paget's disease. Kaplan FS, Singer FS: Paget's disease of bone: Pathophysiology, diagnosis, and management. J Am Acad Orthop Surg 1995;3:336-344. Simon SR (ed): Orthopaedic Basic Science. Rosemont, IL, American Academy of Orthopaedic Surgeons, 1994, pp 129-184.

Question 666

Topic: Biology, Genetics & Bone Healing

In children with moderate to severe osteogenesis imperfecta (OI), intravenous pamidronate therapy has been shown to increase the thickness of cortical bone. This occurs primarily as a consequence of

. increased bone turnover in the cortical area.
. inhibition of osteoclast-mediated bone resorption.
. improved mineralization of cortical bone.
. improved osteoblast organic matrix production.
. improved organization of collagen matrix.

Correct Answer & Explanation

. inhibition of osteoclast-mediated bone resorption.

Explanation

Histologic studies have shown that increased bone turnover is the rule in OI. Pamidronate (and all bisphosphonates) reduce osteoclast-mediated bone resorption. Osteoblastic new bone formation on the periosteal surface of long bones is minimally impaired. With inhibition of osteoclastic bone resorption on the endosteal surface, the cortex of the bone can begin to thicken as it does with normal growth in individuals unaffected by OI. Mineralization and collagen matrix organization are not directly affected by pamidronate. Zeitlin L, Fassier F, Glorieux FH: Modern approach to children with osteogenesis imperfecta. J Pediatr Orthop B 2003;12:77-87. Falk MJ, Heeger S, Lynch KA, et al: Intravenous bisphosphonate therapy in children with osteogenesis imperfecta. Pediatrics 2003;111:573-578.

Question 667

Topic: Biology, Genetics & Bone Healing

What pharmacologic agents are preferred for the treatment of symptomatic active Paget's disease?

Basic Science 2005 Practice Questions: Set 3 (Solved) - Figure 5

. Nasal calcitonin
. Bisphosphonates
. Nonsteroidal anti-inflammatory drugs
. Furosemide
. Antiviral therapy

Correct Answer & Explanation

. Bisphosphonates

Explanation

Recent medical literature supports the use of bisphosphonates as the treatment of choice for active Paget's disease.

Question 668

Topic: Biology, Genetics & Bone Healing

A 42-year-old man reports the recent onset of right hip pain. A radiograph and MRI scan are shown in Figures 38a and 38b. A WBC count, erythrocyte sedimentation rate, and hip aspiration are within normal limits. Management should now consist of

. core decompression.
. biopsy of the femoral head.
. protected weight bearing and observation.
. total hip arthroplasty.
. percutaneous cannulated pin fixation of the femoral neck.

Correct Answer & Explanation

. protected weight bearing and observation.

Explanation

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 corticosteriods are not indicated for treatment. Protected weight bearing until the pain resolves may decrease symptoms while the transient osteoporosis resolves. Potter H, Moran M, Scheider R, et al: Magnetic resonance imaging in diagnosis of transient osteoporosis of the hip. Clin Orthop 1992;280:223-229. Bijl M, van Leeuwen MA, van Rijswijk MH: Transient osteoporosis of the hip: Presentation of typical cases for review of the literature. Clin Exp Rheumatol 1999;17:601-604.

Question 669

Topic: Biology, Genetics & Bone Healing

Figure 17 shows the radiograph of a 2-year-old girl who sustained a fracture of the femur in a fall while walking with her parents. History reveals that this is her third long bone fracture, having sustained a humerus fracture 1 year ago and a fracture of the opposite femur 9 months ago. There is no family history of any similar problem. Examination reveals distinctly blue sclerae, normal appearing teeth, and no skin lesions. What is the most likely cause of this patient's disorder?

Pediatrics Board Review 2001: High-Yield MCQs (Set 2) - Figure 1

. A quantitative defect of type I collagen synthesis
. A deficiency of vitamin D
. Parental abuse
. Abnormal osteoclast function
. Excess excretion of keratin sulfate in the urine

Correct Answer & Explanation

. A quantitative defect of type I collagen synthesis

Explanation

Osteogenesis imperfecta (OI) is a genetically determined disorder of type I collagen synthesis that is characterized by bone fragility. This patient has had three fractures of the long bones by age 2 years, with the last one occurring after relatively minor trauma. The patient's history and clinical features are consistent with a diagnosis of Sillence type IA OI. Type I OI is the mildest and most common form. Inheritance is autosomal-dominant; however, as in this patient, new mutations are frequent. Type I is subclassified into the A type (absence of dentinogenesis imperfecta) and B type (presence of dentinogenesis imperfecta). The sclerae are blue, and the first fractures usually occur in the preschool years after walking has begun. Cells from individuals with type I OI largely demonstrate a quantitative defect of type I collagen; they synthesize and secrete about half the normal amount of type I procollagen. Qualitative mutations that lead to an abnormal type I procollagen molecule result in more severe types of the disorder. There are no indications that this child has been abused. Radiographs of the femur show no evidence of rickets, pyknodysostosis, or osteopetrosis. Morquio syndrome, characterized by excess excretion of keratin sulfate in the urine, is not associated with bone fragility. Kocher MS, Shapiro F: Osteogenesis imperfecta. J Am Acad Orthop Surg 1998;6:225-236. Sillence DO, Senn A, Danks DM: Osteogenesis imperfecta: An expanding panorama of variants. Clin Orthop 1981;159:11-25.

Question 670

Topic: Biology, Genetics & Bone Healing

A female cross-country runner has an insidious onset of right groin pain. Radiographs of the right hip reveal a tension-side stress fracture. History reveals that she was treated for a "foot" fracture 1 year ago. In addition to performing internal fixation of the femoral neck, which of the following should be obtained?

. Menstrual history
. Family history
. Serum calcium level
. MRI of the hip
. Contralateral hip radiograph

Correct Answer & Explanation

. Menstrual history

Explanation

Stress fractures in female long distance runners are frequently associated with the Female Athletic Triad. The triad consists of osteoporosis, amenorrhea, and altered eating habits. A thorough menstrual history, including age of menarche, history of amenorrhea, and use of oral contraceptives, is imperative. Amenorrhea leads to osteoporosis and predisposes the athlete to fractures. An MRI of the hip is not necessary because a fracture is evident on the radiograph. Serum calcium levels are normal in osteoporosis, a family history would be noncontributory, and it is highly unlikely that a contralateral hip radiograph will yield useful information. Bennell KL, Malcolm SA, Thomas SA, et al: Risk factors for stress fractures in track and field athletes: A twelve-month prospective study. Am J Sports Med 1996;24:810-818.

Question 671

Topic: Biology, Genetics & Bone Healing

Which of the following accurately defines changes in Vitamin D requirements as the result of aging?

. Increase because of decreased levels of serum 25(OH)D
. Increase, but calcium requirements remain the same
. Remain the same, with a decrease in levels of serum 1,25(OH)D
. Remain the same, but calcium requirements increase.
. Decrease, with decreasing circulating PTH levels

Correct Answer & Explanation

. Increase, but calcium requirements remain the same

Explanation

Older individuals ingest less Vitamin D and are unable to generate as much as younger people via the skin in response to ultraviolet exposure; thus, there is a decrease in the levels of serum 25(OH) D. This reduction in 25(OH)D leads to a reduction in calcium absorption. There is also decreased conversion in the kidney of 25(OH)D to 1,25(OH)D. This all leads to an increase in the daily requirements of both calcium and Vitamin D. It also results in a responsive increase in PTH secretion in the elderly, as well as renal function impairment and possible renal resistance to PTH. Dawson-Hughes B, Harris SS, Krall EA, et al: Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age and older. N Engl J Med 1997;337:670-676. Recker RR, Hinders S, Davies M, et al: Correcting calcium nutritional deficiency prevents spine fractures in elderly women. J Bone Miner Res 1996;11:1961-1966.

Question 672

Topic: Biology, Genetics & Bone Healing

Figure 11 shows the radiograph of a 2-year-old child with marked genu varum and tibial bowing. Based on these findings, what is the best initial course of action?

Pediatrics 2007 Practice Questions: Set 1 (Solved) - Figure 27

. Obtain serum phosphorous, calcium, and alkaline phosphatase levels.
. Obtain a scanogram to assess for limb-length discrepancy.
. Perform bilateral valgus osteotomies to correct the deformities.
. Measure the child for a varus prevention orthosis.
. Educate the family about physiologic genu varum and conduct a follow-up examination in 6 months.

Correct Answer & Explanation

. Obtain serum phosphorous, calcium, and alkaline phosphatase levels.

Explanation

The radiograph shows multiple wide physes, consistent with a diagnosis of rickets. A low serum phosphorous level and an elevated alkaline phosphatase level are the hallmarks in diagnosing familial hypophosphatemic Vitamin D-resistant rickets. Serum calcium is usually normal or low normal. This disease is inherited as an X-linked dominant trait and usually presents at age 18 to 24 months. The disease results from a poorly defined problem with renal phosphate transport in which normal dietary intake of vitamin D is insufficient to achieve normal bone mineralization. Renal tubular dysfunction is associated with urinary phosphate wasting. Treatment involves oral phosphate supplementation, which can cause hypocalcemia and secondary hyperparathyroidism. To prevent associated problems, high doses of Vitamin D are administered. While obtaining a scanogram may be clinically indicated in an associated limb-length discrepancy, and subsequent corrective surgery may be indicated, either of these choices would not be the first course of action. An orthosis may slow the progression of genu varum in this disorder but is less important than establishing the correct diagnosis to begin pharmacologic treatment. This amount of varum and tibial bowing far exceeds the normal limits of physiologic genu varum. Skeletal dysplasias usually are not associated with abnormal laboratory values. Herring JA: Metabolic and endocrine bone diseases, in Tachdjian's Pediatric Orthopaedics, ed 3. New York, NY, WB Saunders, 2002, pp 1685-1743.

Question 673

Topic: Biology, Genetics & Bone Healing

A 74-year-old woman has had acute medial right knee pain for the past 3 months. She denies any history of trauma or previous problems. Coronal and sagittal MRI scans are shown in Figures 11a and 11b. What is the most likely diagnosis?

. Osteoarthritis
. Rheumatoid arthritis
. Medial meniscal tear
. Osteonecrosis
. Transient osteoporosis

Correct Answer & Explanation

. Osteonecrosis

Explanation

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. Kidwai AS, Hemphill SD, Griffiths HJ: Spontaneous osteonecrosis of the knee reclassified as insufficiency fracture. Orthopedics 2005;28:236,333-336. Soucacos PN, Xenakis TH, Beris AE, et al: Idiopathic osteonecrosis of the medial femoral condyle: Classification and treatment. Clin Orthop 1997;341:82-89.

Question 674

Topic: Biology, Genetics & Bone Healing

A 3-year-old child has bilateral genu varum and short stature. Radiographs show physeal widening and generalized osteopenia. The femora and tibiae show anterolateral bowing. Laboratory studies show low normal serum calcium values, significantly decreased serum phosphate levels, and normal parathyroid hormone (PTH), alkaline phosphatase, and vitamin-D levels. These findings are consistent with

. nutritional rickets.
. renal osteodystrophy.
. primary hyperparathyroidism.
. hypophosphatasia.
. vitamin D-resistant rickets.

Correct Answer & Explanation

. vitamin D-resistant rickets.

Explanation

Children with vitamin D-resistant rickets are short in stature and have genu varum, physeal widening, and generalized osteopenia. The abnormality in inherited vitamin D-resistant rickets is the renal tubule's inability to resorb phosphate leading to hypophosphatemia. Laboratory findings in the condition are normal or near normal serum calcium values, significantly decreased serum phosphate levels, elevated alkaline phosphatase levels, and normal PTH and vitamin-D levels. The most common form is inherited as an X-linked dominant trait. Nutritional rickets has a normal or low serum phosphate levels, normal or low serum calcium values, and decreased levels of 25(OH) vitamin D and 1,25-dihydroxyvitamin D. Hypophosphatasia is a rare condition characterized by a deficiency of alkaline phosphatase in the serum and tissues, leading to generalized abnormal mineralization of bone. Primary hyperparathyroidism usually is caused by a parathyroid adenoma, and the child generally has abdominal problems and hypercalcemic crisis. Laboratory findings include elevated serum calcium values, alkaline phosphatase levels, and PTH levels, and decreased serum phosphate levels. Children with renal osteodystrophy tend to have genu valgum, and laboratory findings include elevated serum phosphate, alkaline phosphatase, and PTH levels, and low serum calcium values. Findings of renal disease include elevated BUN and creatinine. Herring JA: Metabolic and endocrine bone diseases, in Herring JA (ed): Tachdjian's Pediatric Orthopaedics, ed 3. Philadelphia, PA, WB Saunders, 2002, pp 1686-1710.

Question 675

Topic: Biology, Genetics & Bone Healing

Gaucher's disease is manifested by reticuloendothelial system macrophage accumulation of

Basic Science 2002 Practice Questions: Set 1 (Solved) - Figure 34

. cholesterol.
. hydroxyproline.
. calcium pyrophosphate.
. homogentisic acid.
. glucocerebroside.

Correct Answer & Explanation

. glucocerebroside.

Explanation

Gaucher's disease is characterized by macrophage accumulation of glucocerebroside that is caused by a deficiency of lysosomal enzyme glucocerebrosidase. It is an autosomal-recessive trait and is most commonly found in Ashkenazi Jews. Orthopaedic surgeons see patients with Gaucher's disease usually because of osteonecrosis of the hip. Calcium pyrophosphate is associated with pseudogout. Hydroxyproline is a breakdown product of collagen and is found in high levels in patients with Paget's disease. Homogentisic acid is associated with ochronosis (alkaptonuria). Beatty JH: Orthopaedic Knowledge Update 6. Rosemont, IL, American Academy of Orthopaedic Surgeons, 1999, pp 247-252. Goldblatt J, Sacks S, Beighton P: The orthopedic aspects of Gaucher disease. Clin Orthop 1978;137:208-214.

Question 676

Topic: Biology, Genetics & Bone Healing

A 32-year-old female presents with knee pain. Radiographs show an eccentric, lytic epiphyseal lesion. Biopsy shows multinucleated giant cells and mononuclear stromal cells. Denosumab therapy is considered. What is the precise mechanism of action of Denosumab?

. Binds to RANKL, preventing interaction with RANK
. Binds directly to RANK on osteoclasts
. Inhibits osteoprotegerin production
. Inhibits bisphosphonate absorption in the gut
. Directly inhibits vascular endothelial growth factor (VEGF)

Correct Answer & Explanation

. Binds to RANKL, preventing interaction with RANK

Explanation

Denosumab is a monoclonal antibody that specifically binds to RANKL (Receptor Activator of Nuclear factor Kappa-B Ligand). By binding to RANKL, it prevents it from interacting with the RANK receptor on the surface of osteoclasts and giant cells, thereby profoundly inhibiting osteoclastogenesis and tumor-associated bone lysis in giant cell tumors.

Question 677

Topic: Biology, Genetics & Bone Healing

A 45-year-old male sustains a severe open distal femur fracture. Following debridement, a massive bone defect is treated with the induced membrane (Masquelet) technique. What is the peak time to harvest or graft the induced membrane for optimal vascular endothelial growth factor (VEGF) and bone morphogenetic protein-2 (BMP-2) expression?

. 2 weeks
. 4 weeks
. 8 weeks
. 12 weeks
. 16 weeks

Correct Answer & Explanation

. 4 weeks

Explanation

The induced membrane created in the Masquelet technique possesses peak osteogenic and angiogenic properties, including maximum expression of VEGF, BMP-2, and TGF-beta, at approximately 4 weeks. Most surgeons perform the second-stage bone grafting between 4 and 6 weeks to capitalize on this biological peak.

Question 678

Topic: Biology, Genetics & Bone Healing
During the process of secondary fracture healing, endochondral ossification is paramount. During the soft callus phase, chondrocytes proliferate and eventually undergo hypertrophy. Which type of collagen is uniquely and predominantly synthesized by hypertrophic chondrocytes to facilitate matrix calcification?
. Type I collagen
. Type II collagen
. Type III collagen
. Type IX collagen
. Type X collagen

Correct Answer & Explanation

. Type X collagen

Explanation

Hypertrophic chondrocytes are the hallmark of the transition zone in endochondral ossification. They cease producing Type II collagen (which is characteristic of proliferating chondrocytes) and exclusively synthesize Type X collagen. Type X collagen alters the extracellular matrix to allow for calcification and subsequent vascular invasion, paving the way for osteoblasts to lay down woven bone.

Question 679

Topic: Biology, Genetics & Bone Healing

A 55-year-old male with long-standing, poorly controlled type II diabetes presents with an acutely swollen, erythematous, and warm left foot. He denies any penetrating trauma or fevers. Radiographs show fragmentation and early subluxation of the tarsometatarsal joints. Which of the following mediators is most directly responsible for driving the aggressive osteoclastic bone resorption seen in the acute, active phase of this disease process?

. Interleukin-10 (IL-10)
. Receptor activator of nuclear factor kappa-B ligand (RANKL)
. Osteoprotegerin (OPG)
. Transforming growth factor beta (TGF-beta)
. Vascular endothelial growth factor (VEGF)

Correct Answer & Explanation

. Receptor activator of nuclear factor kappa-B ligand (RANKL)

Explanation

Acute Charcot neuroarthropathy is characterized by an exaggerated pro-inflammatory response (mediated by TNF-alpha and IL-1) leading to marked upregulation of RANKL. RANKL binds to the RANK receptor on osteoclast precursors, driving massive osteoclastogenesis and the aggressive bone resorption/fragmentation classically seen in Eichenholtz Stage 1. Osteoprotegerin (OPG) acts as a decoy receptor to bind RANKL and inhibit this process, but the balance is shifted toward RANKL in acute Charcot.

Question 680

Topic: Biology, Genetics & Bone Healing

Nitrogen-containing bisphosphonates, such as alendronate, are frequently prescribed to prevent osteoporotic fractures. What is the primary molecular mechanism by which these drugs inhibit osteoclast-mediated bone resorption?

. Direct inhibition of the RANKL-RANK interaction
. Binding to the Wnt co-receptor LRP5 to prevent osteoblast apoptosis
. Inhibition of farnesyl pyrophosphate synthase in the mevalonate pathway
. Cleavage of SNAP-25 in the presynaptic terminal
. Direct inhibition of the lysosomal enzyme cathepsin K

Correct Answer & Explanation

. Inhibition of farnesyl pyrophosphate synthase in the mevalonate pathway

Explanation

Nitrogen-containing bisphosphonates (like alendronate, zoledronate, and risedronate) enter osteoclasts and inhibit the enzyme farnesyl pyrophosphate synthase (FPPS), a key enzyme in the mevalonate pathway. This prevents the synthesis of isoprenoid lipids (such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate), which are essential for the prenylation of small GTPases (like Ras, Rho, and Rab). Without prenylation, these proteins cannot anchor to the cell membrane to form the ruffled border, causing osteoclast dysfunction and eventual apoptosis. Non-nitrogen-containing bisphosphonates work by forming toxic ATP analogues.

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