Biology, Genetics & Bone Healing MCQs

Osteoporosis is defined as a chronic, progressive disease characterized by low bone mass and decreased bone strength. Risk factors for osteoporosis include increasing age, postmenopausal women, long-term calcium deficiency, and excessive steroid or alcohol abuse. T-scores are defined as standard deviations from normal peak bone mass (young adults), whereas Z-scores compare bone density of the same age and size. Osteoporosis is defined as a T-score of -2.5 or below as defined by the WHO, and osteopenia is defined as a T-score between -1.0 and -2.5. Z-scores are not used to stratify patients into categories of "osteopenia" or "osteoporosis" in elderly patinets. They are used to aid in the diagnosis of metabolic bone disease in young patients.

DISCUSSION: Recent medical literature supports the use of bisphosphonates as the treatment of choice for active Paget’s disease.REFERENCE: Delman PD, Meunier PJ: The management of Paget’s disease.  N Eng J Med 1997;336:558-566.

DISCUSSION: Cigarette smoking has been directly linked to pseudarthrosis in spinal fusions.  The direct mechanism of action is diminished revascularization of cancellous bone graft.  Additionally, a smaller area of revascularization is seen in these grafts, as well as an increased area of necrosis.  Increased activity of osteoblasts would result in more bone production.  Increased activity of osteocytes would not affect the fusion because osteocytes are mature bone cells.REFERENCE: Daftari TK, Whitesides TE Jr, Heller JG, et al: Nicotine on the revascularization of bone graft: An experimental study in rabbits.  Spine 1994;19:904-911.

DISCUSSION: The studies reveal significant heterotopic ossification that appears to be mature.  Following resection, the most reliable way to prevent recurrence is with low-dose external-beam radiation therapy.  Bisphosphonate therapy can be considered; however, when terminated, heterotopic bone may reform.  Heterotopic ossification is unrelated to the patient’s endocrine status and is not associated with any metabolic abnormalities.REFERENCES: Moore K, Goss K, Anglen J: Indomethacin versus radiation therapy for prophylaxis against heterotopic ossification in acetabular fracture.  J Bone Joint Surg Br 1998;80:259.Stover S, Niemann K, Tullos J: Experience with surgical resection of heterotopic bone in spinal cord injury patients.  Clin Orthop 1991;263:71-77.

Bisphosphonates are antiresorptive agents that act by targeting osteoclatic bone resorption. Calcitonin also inhibits osteoclastic bone resorption. Excessive cortisol decreases intestinal calcium absorption, increases calcium loss from the kidney, inhibits bone matrix formation, and causes secondary hyperparathyroidism. TNF-a inhibits osteoblastic activity and enhances osteoclastic bone resorption. Intermittent administration of PTH isoforms is anabolic, whereas persistent elevated levels of PTH promotes bone resorption.

DISCUSSION: As a side effect of treatment, phenytoin induces osteomalacia, or rickets, in growing children, through interference with metabolism of vitamin D.  Oral supplementation of vitamin D can minimize this effect in patients who are undergoing prolonged treatment with phenytoin.REFERENCE: Chung S, Ahn C: Effects of anti-epileptic drug therapy on bone mineral density in ambulatory epileptic children.  Brain Dev 1994;16:382-385.

Gabapentin acts by inhibiting presynaptic calcium channels, thus preventing the release of neurotransmitters.Gabapentin (also known as Neurontin) is a medication that is commonly used to treat neuropathic pain. It acts by binding the alpha2delta subunit of voltage-dependent calcium channels on the presynaptic membrane. This serves to increase GABA synthesis, as well as inhibit the release of excitatory neurotransmitters. These neurotransmitters are believed to be part of the pathway leading to neuropathic pain.Bennett et al. provide a review of the pharmacology of gabapentin for the use of neuropathic pain. They note effective antihyperalgesic and antiallodynic properties of gabapentin but not significant anti-nociceptive action. Among patients with neuropathic pain they found an average pain score reduction of 2.05 points on an 11 point Likert scale, which compared favorably to placebo.Mehta et al. explored outcomes of gabapentin and pregabalin (Lyrica) for use in patients with spinal cord injury. Both agents were found to decrease pain and secondary conditions such as sleep disturbance. They did not directly compare these agents to other analgesic medications.Guy et al. present a meta-analysis of the use of anticonvulsants (such as gabapentin) to treat pain in patients with spinal cord injury. Large effect size was seen in 4 of 6 studies looking at the effectiveness of gabapentin.Illustration A show the mechanism of currently available antiepileptic drugs (AEDs) that target several molecules at the excitatory synapse. Gabapentin and pregabalin bind to the a2d subunit of voltage-gated Ca2+ channels, which is thought to be associated with a decrease in neurotransmitter release.Incorrect Answers

The extracellular matrix consists of water, proteoglycans, and collagen. Water makes up the majority (approximately 65% to 80%) of wet weight; 95% of the collage is type II with much smaller amounts of other collagens, including types IV, VI, IX, X, and XI. The exact functions of these other collagens are unknown, but they are believed to be important in matrix attachment and stabilization of the diameter of collagen fibrils.

Whereas all of the factors will have an impact on frame rigidity and stability, the single biggest factor is the pin diameter because it has an exponential effect.Which of the following clinical scenarios represents the strongest indication for locked plating technique in a 70-year-old woman?Segmentally comminuted ulnar fractureSimple diaphyseal fracture of the humerusTransverse midshaft displaced clavicle fracturePeriprosthetic femur fracture distal to a well-fixed total hip arthroplastySchatzker 2 fracture of the tibia with severe joint depression and comminutionLocking screw fixation is a relatively new option in the armamentarium of orthopaedic surgeons treating fractures. The understanding of the biomechanics, implications to healing, and optimal indications and surgical techniques is still in evolution. A periprosthetic proximal femur fracture with a stable prosthesis is best treated with open reduction and internal fixation with locking proximal fixation with or without cerclage cables. Diaphyseal fractures treated with compression plating or bridge plating can be treated well with conventional implants unless osteoporosis is severe. An AO/OTA B-type partial articular fracture is also better suited to standard buttress plating with periarticular rafting lag screws. Locking fixation is not always required for a transverse displaced midshaft clavicle fracture.What is the post-amplification product of reverse transcription polymerase chain reaction (RT-PCR)?RNADNAProteinMitochondriaImmunoglobulinsReverse transcription polymerase chain reaction (RT-PCR) is a variant of polymerase chain reaction (PCR) used in molecular biology to generate many copies of a DNA sequence from fragments of RNA. The RNA strand is first reverse transcribed into its DNA complement, followed by amplification of the resulting DNA using polymerase chain reaction. Polymerase chain reaction amplifies short segments of DNA by using the temperature stable DNA polymerase enzyme.A 63-year-old woman falls from standing and lands on her right hand. She complains of deformity and wrist pain. Radiographs are provided in Figure A. Following closed reduction, the patient inquires whether she has osteoporosis and if she is likely to have another fracture. In counselling the patient, which of the following is the strongest predictor for a future fracture from low energy trauma?Bone mineral density T-score < -2.5Low vitamin D levelsFamily history of osteoporosisHistory of a prior fragility fractureTen year history of oral prednisone useEach of the answer choices is a risk factor for subsequent fragility fracture, but patient history of a prior fragility fracture is the strongest predictor.Bouxsein et al reviews the proper care, diagnosis, and prevention of fragility fractures. History of a fragility fracture is the greatest predictor of a future fracture from low energy trauma. Appropriate care includes not only treatment of the fracture itself, but also proper evaluation to identify the etiology of the fracture and appropriate intervention to rectify the underlying pathology. Evaluation includes bone densitometry, lab testing of Vitamin D and calcium.A T-score compares your bone density to the optimal peak bone density for your gender. It is reported as number of standard deviations below the average. A T-score of -1 to -2.5 is considered osteopenia, and a risk for developing osteoporosis. A T- score of less than -2.5 is diagnostic of osteoporosis.Long-term alendronate (Fosamax) use for osteoporosis has been associatedwith which of the following?ScurvyDetached retinaUterine carcinomaOsteonecrosis of the femoral headDiaphyseal femoral insufficiency fracturesAlendronate is a bisphosphonate that inhibits the ruffled border of the osteoclast. When used long term, this class of medication prevents the normal bone remodeling process. Long-term use has recently been shown to be associated with insufficiency fractures of the femur. Osteonecrosis of the jaw has been described but not in other anatomic locations. Scurvy occurs because of a lack of vitamin C and use of bisphosphonates is not associated withuterine cancer or a detached retina.Implants composed of polylactic acid are excreted by what system after they are absorbed?HepaticRenalRespiratoryGastrointestinalPolylactic acid suture and suture anchors are popular bioabsorbable orthopaedic implants. This material undergoes hydrolysis of the ester background in vivo. Resulting lactic acid enters the tricarboxylic acid (Krebs)cycle and is excreted as carbon dioxide by the lungs. Polyglycolic acid and poly(p- dioxanone) may also be excreted by the kidneys.A patient sustains a grade III medial collateral ligament injury. One year later, when compared to collagen in an uninjured ligament, an increase is likely in thegross number of fibers.proportion of type III fibers.cross-linking.mass and diameter of fibers.Studies on animal models have shown that there is a change in collagen fiber type and distribution early in the healing process. There is a higher portion of type III fibers than innormal ligament initially, but this ratio returns to normal about 1 year after the injury occurs. Healing ligaments show an increased number of collagen fibers, but the number of mature collagen cross-links is45% of predicted value after 1 year. There is also a decrease in the mass and diameter of the collagen fibers.Sclerostin and dickkopf-1 (Dkk-1) are direct inhibitors of what pathway related to bone and/or cartilage regulation?Bone morphogenetic protein (BMP)/SMAD pathwayReceptor activator of nuclear factor kappa beta (RANK)/RANK ligand (RANKL) pathwayWnt/Beta-catenin (ß-catenin) pathwayParathyroid hormone (PTH) pathwayDkk-1 and sclerostin are proteins that inhibit the binding of the Wnt molecule to receptors LRP5/6. In the absence of sclerostin and Dkk-1, Wnt binds to its receptor, which in turn inhibits phosphorylation of the ß-catenin. The unphosphorylated ß-catenin then builds up in the cytoplasm of the cell, allowing it to be transported to the nucleus of the cell. Once in the nucleus, ß- catenin will lead to upregulation of a series of proteins involved in osteoblast formation differentiation. Knocking out or inhibiting sclerostin or Dkk-1 results  in increased bone mass secondary to constitutive activation of the Wnt/ß- catenin pathway. The other responses are not directly affected by Dkk-1 or sclerostin. RANKL and RANK are expressed on osteoblasts and osteoclasts, respectively, and are involved in osteoblast-mediated osteoclast activation. BMPs work through SMADs to cause osteoblastic differentiation, and there is reported crosstalk between the Wnt and BMP pathways (but this is an indirect link). Finally, PTH at physiologic levels binds to osteoblasts, causing a series of events that lead to osteoblast-mediated osteoclast activation and subsequent increased bone resorption.During endochondral ossification of the growth plate, the process that most contributes to the longitudinal growth of long bones ischondrocyte apoptosis.chondrocyte hypertrophy.chondrocyte proliferation.growth plate matrix synthesis.The growth plate is divided into 5 distinct zones: reserve, proliferative, maturation, hypertrophy, and vascular invasion. During growth-plate chondrocyte hypertrophy, intracellular volume and an increase in chondrocyte height are responsible for most growth of long bones. Other factors that contribute to bone growth are chondrocyte proliferation and matrix synthesis, but to a lesser degree than chondrocyte hypertrophy. Growth plate chondrocytes undergo programmed cell death (apoptosis) after hypertrophytakes place.Bacterial resistance to tetracycline is confirmed by ribosome protection, tetracycline modification, andaltered RNA polymerase.altered membrane binding protein.increased drug efflux.DNA gyrase mutation.Mutations of bacterial DNA gyrase can decrease the effectiveness of quinolones. Altered membrane-binding protein is observed with resistance to ?-lactam antibiotics. Tetracyclines are antibiotics that inhibit bacterial growth by stopping protein synthesis. Three specific mechanisms of tetracyclineresistance have been identified: increased tetracycline efflux, ribosome protection, and tetracycline modification. Alteration of RNA polymerase is found in resistance to rifampin.A 14-year-old boy has failed physical therapy management for Scheuermann kyphosis, and an extension thoracolumbosacral orthosis brace is recommended. The boy and his parents are told that the brace will force his thoracic spine into normal sagittal alignment and put the anterior vertebral bodies of the thoracic segment into tension, which will induce bone growth and normalization of wedge- shapedvertebrae. What name is associated with this process?Hooke's lawKirchhoff's lawWolff's lawHeuter-Volkmann principleThe Heuter-Volkmann principle shows that bone placed in longitudinal tension will tend to stimulate longitudinal growth, and that compressive longitudinal forces inhibit longitudinal growth, making this response the best choice. Hooke's law relates to stress being proportional to strain and is not directly related to bone growth. Kirchhoff's laws apply to electrical circuit design. Wolff's law states that bone remodels in response to mechanical stress, with the correlate that increased stress causes increased growth, and decreased stress leads to bone loss.A tendon repair is thought to be weakest during which phase of tendon healing?InflammatoryProliferationMaturationRemodelingHealing after a tendon repair or rupture has the following stages: inflammatory, cellular proliferation, and remodeling. During the inflammatory phase, neutrophils and macrophages migrate into the injury site and release chemotactic factors that recruit fibroblasts. A tendon is thought to be weakest5 to 21 days after repair, which coincides with the inflammatory phase. During the proliferative phase, inflammatory cells secrete cytokines and growthfactors (platelet-derived growth factor, insulin-like growth factor, bone morphogenetic protein (BMP)-12 and BMP 13, and transforming growth factor- beta) that promote differentiation of fibroblasts. Fibrosis and decreased cellularity are the hallmarks of the remodeling stage.A 4-year-old boy has bilateral genu varum and is in the fifth percentile for height for his age. A younger sister has less severe genu varum. Radiographs reveal physeal cupping and widening on both the distal femur and proximal tibia. Laboratory studies show sodium 145 mEq/L (reference range, 136-142 mEq/L), potassium 4.0 mEq/L (reference range, 3.5-5.0 mEq/L), calcium 9.0 mg/dL (reference range, 8.2-10.2 mg/dL), phosphorous 2 mg/dL (reference range, 4-

Numerous reports suggest an increased frequency of nutritional rickets in the US in children with dark skin pigmentation who are breast fed past 6 months of age without vitamin D supplementation. Nutritional rickets is rare in light-skinned children or those who are formula fed.

DISCUSSION: Transcription factors regulate the activation or repression of cartilage-specific genes. Sox-9, considered a major regulator of chondrogenesis, regulates several cartilage-specific genes during endochondral ossification, including collagen types II, IV, and XI and aggrecan.REFERENCES: Li J, Sandell LJ: Transcriptional regulation of cartilage-specific genes, in Rosier RN, Evans C (eds): Molecular Biology in Orthoapedics,  Rosemont, IL, American Academy of Orthopaedic Surgeons, 2002, pp 21-24.Sandell LJ: Genes and gene expression.  Clin Orthop 2000;379:S9-S16.

DISCUSSION: 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.REFERENCES: 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.Barrow GW, Saha H: Menstrual irregularity and stress fractures in collegiate female distance runners.  Am J Sports Med 1988;16:209-216.

The mechanism by which bisphosphonates act is by inhibiting osteoclasts. One mechanism of bisphosphonates is to cause osteoclast apoptosis. Another mechanism of bisphosphonates is to disrupt the cytoskeleton of osteoclasts, resulting in loss of the ruffled border. The uncoupling of bone resorption and bone formation with decreased bone resorption results in increased bone mineralization. This translates into fewer fractures in patients with osteogenesis imperfecta and improved quality of life.

This is prospective cohort study with Level-II evidence.Level of evidence provides guidance to the study quality. It is used to assess therapeutic studies (as with this question), prognostic studies, diagnostic studies and economic or decision models. When determining the level of evidence, readers must critically appraise the study question, treatment, intervention and outcomes of the study design. Level-II therapeutic studies consist of well-designed prospective cohort studies, poor-quality randomized controlled trials (follow-up less than 80%) and systematic review of Level-II studies or non-homogenous Level-I studies.Wright et al. provided an excellent summary of clinical research study level of evidence. This has been provided as Illustration A.Illustration A shows a chart of level of evidence. There is a column for each type of study which corresponds to a row that outlines the level of evidence based on studydesign.Incorrect Answers:Low serum phosphate and normal calcium levels are found in what common etiology of hereditary rickets?X-linked hypophosphatemicVitamin D-dependent, type IVitamin D-dependent, type IIAutosomal dominant hypophosphatemicJansen's metaphyseal chondrodysplasiaLow serum phosphate and normal calcium levels are found in X-linked hypophosphatemic rickets.X-linked hypophosphatemic rickets is the most common form of hereditary rickets. It is an X-linked dominant disorder which has been linked to the PHEX gene. Laboratory findingsof this disorder include low serum phosphate, normal serum calcium and 25 hydroxycholecalciferol levels, and inappropriately low 1,25-dihydroxyvitamin D3.Carpenter et al. showed hypophosphatemic rickets was initially referred to as “vitamin D resistant rickets” due to its lack of response to therapeutic vitamin D. Current treatment with activated vitamin D metabolites (calcitriol oralfacalcidol) and phosphate salts have been shown to help with this condition.Illustration A shows an insufficiency fracture of the proximal tibia in an adult patient with X-linked hypophosphatemic rickets. A stress fracture on the medial tibia may be a presenting feature of untreated disease.Incorrect Answers:receptor (PTHR1).A healthy patient undergoes routine pre-operative laboratory testing and is found to have a leukocyte count of 1.5 × 10(9) cells/L. When the historical records are examined, this is found to be the patients base-line level over a period of years. Which of the following statements is most likely to be true:The patient is at a significantly higher risk of surgical infectionThe patient is more likely to be of African than of European descentThe patient is more likely to be of European than of Middle Eastern descentThe patient is more likely to be a non-athlete than an athleteThe patient is more likely to be female than maleThe clinical presentation is consistent with Benign Ethnic Neutropenia, a condition in which a patient has chronic, benign, inborn and lifelong absolute neutrophl count below population mean. This condition is found in the U.S. to be most common in African- Americans, some groups of Middle Eastern patients, males, children under 5 years old, and athletes compared to non- athletes.A standardized level at present for abnormally low absolute neutrophil count (ANC) is below 1.5 x 10(9) cells/L, however this may not have clinical or scientific relevance as a cutoff point, particularly in the affected Ethnic groups. Fewer than 1% of all populations have absolute neutrophil count < 1.0 X 10(9) cells/L. Most patients in the affected ethnic groups with low ANC and no associated history or symptoms are not expected to have any increased risk of infection or adverse effect. Smoking was also associated with higher leukocyte and neutrophil counts but proportionately lower increase in African-American patients. One hypothesis for the increased prevalence of B.E.N. in patients of African descent is a theorized evolutionary protection against malaria, thoughit remains unclear if this is causal or just correlative.Haddy et al. provide an excellent scientific review of B.E.N. and emphasize the importance of recognizing this most common form of neutropenia.Eichner et al. review B.E.N. in the setting of sports medicine and state the relative increase of these lab findings in athletes vs non-athletes.Hsieh et al. provide an extensive cross-sectional population study focused on the prevalence of Benign Ethnic Neutropenia in the U.S. They reviewed 25,222 participants in the National Health and Nutrition Examination Survey 1yr ofage or older from 1999-2004, and detail the association of this condition with age, sex, ethnicity, and smoking status.Denic et al. analyzed neutrophil count in a healthy Arab population in the U.A.E. and found low neutrophil counts in this population with a distribution suggestive, but not definitively, of an autosomal dominant inheritance. They also discuss the hypothesized association of B.E.N. and malaria infection.Incorrect answers:

A muscle's response to injury can be divided into 4 phases: necrosis, inflammation, repair, and fibrosis. Muscle fibrosis occurs at the same time as muscle regeneration and has been shown to involve TGF-ß1. IGF-1 and bFGF are important trophic factors in muscle regeneration. Bone morphogenetic protein has several functions including bone and cartilage regeneration.

Mutations of PHEX are responsible for X-linked hypophosphatemic rickets. Mutations of CLCN7 and TC1RG1 cause osteopetrosis. COLIA1 or COLIA2 mutations cause osteogenesis imperfecta (OI) which has literally hundreds of genotypes causing a more limited number of phenotypes as described by Silence. GNAS1 is the gene mutation of fibrous dysplasia that results in an activating mutation of the GSalpha1 protein. TGF-BR2 or FBN1 cause Marfan syndrome.

Bisphosphonate therapy combined with invasive dental work increases the risk for development osteonecrosis of the jaw.Bisphosphonates are a class of drugs that prevent bone mass loss by inhibiting osteoclast resorption. They are used in the treatment of vertebral compression fractures, non-vertebral fragility fractures, osteogenesis imperfecta, multiple myeloma, and avascular necrosis. Because bisphosphonates have been associated with osteonecrosis of the jaw, it is suggested that all invasive dental work be completed prior to initiation of treatment.Pazianas et al. (2011) review the safety profile of bisphosphonates. Specifically, they cite gastrointestinal discomfort, atypical femur fractures, osteonecrosis of the jaw, ocular inflammation, and musculoskeletal pain as common side effects. They state there is limited evidence surrounding bisphosphonate's association with esophageal cancer and atrial fibrillation.Pazianas et al. (2007) reviewed 11 publications that reported 26 cases of osteonecrosis of the jaw following initiation of bisphosphonate treatment. Age >60 years, female sex, and previous invasive dental treatment were the most common characteristics of those who developed ONJ.Illustration A shows the various bisphosphonates and their mechanisms of action. Illustration B shows an example of osteonecrosis of the jaw, a side effect that has been linked to bisphonphonate treatment.Incorrect Answers:

Anorexia athletica is a newer term that may generally replace the "triad" of disordered eating, menstrual dysfunction, and osteoporosis. True osteoporosis is actually relatively uncommon in the female athlete, and thus the traditional diagnostic criteria are rarely met. In anorexia athletica, multiple signs and symptoms are used to reach the diagnosis. Specifically, however, a diagnosis of anorexia athletica requires the absence of any affective disorder, such as depression.

Denosumab is FDA-approved for the treatment of osteoporosis in men and women. It inhibits the formation, function and survival of osteoclasts (OC). It does not bind to calcium hydroxyapatite. At 1-year after the initial dose, tissue levels are non-detectable.Denosumab is a human monoclonal antibody against RANKL. By binding RANKL, it prevents interaction of RANKL with RANK (on OC and osteoclast precursors, OCP), and inhibits OC-mediated bone resorption, and the formation, function and survival of OC. In contrast, bisphosphonates bind to calcium hydroxyapatite in bone, and decrease resorption by decreasing function and survival (but not formation) of OC.Vaananen et al. reviewed the cell biology of OC. During bone resorption, 3 membrane domains appear: ruffled border, sealing zone and functional secretory domain. The resorption cycle starts with migration, bone attachment, polarization (formation of membrane domains), dissolution of hydroxyapatite, degradation of organic matrix, removal of degradation products from resorption lacuna, and apoptosis of the OC or return to the non-resorbing stage.Boyce et al. reviewed the regulation of osteoclasts and their functions. OCPs are held in bone marrow by chemokines e.g. stroma-derived factor-1 (SDF1) and attracted to blood by sphingosine-1 phosphate (S1P) (increased in synovial fluid of patients with RA). All aspects of osteoclast formation and functions are regulated by M-CSF and RANKL. More recent studies indicate that osteoclasts and their precursors regulate immune responses and osteoblast formation and functions by means of direct cell-cell contact through ligands and receptors, such as ephrins and Ephs, and semaphorins and plexins, and through expression of clastokines.Warriner and Saag reviewed the diagnosis and treatment of osteoporosis. They defined osteoporosis as T-score of = -2.5 or a history of fragility fracture. Incident hip and vertebral fractures increase future risk of these fractures (hazard ratio 7.3 and 3.5, respectively).Cummings et al. compared subcutaneous denosumab (60mg every 6mths) vs placebo in prevention of fractures in 7868 osteoporotic (T-score -2.5 to -4.0) postmenopausal women. They found that denosumab reduced risk of vertebral fracture by 68% (risk ratio, 0.32), hip fracture by 40% (hazard ratio 0.6), nonvertebral fracture by 20% (hazard ratio 0.8). There was no increased risk of cancer, infection, delayed fracture healing, cardiovascular disease, osteonecrosis of the jaw or adverse reactions. They concluded that it was useful for reduction of fractures in osteoporotic women.The video shows the action of denosumab (prolia). Illustration A shows the different osteoclast zones.Incorrect Answers:

DISCUSSION: Nutritional rickets is associated with decreased dietary intake of Vitamin D, resulting in low levels of Vitamin D that result in decreased intestinal absorption of calcium and low to normal serologic levels of calcium. To boost serum calcium levels, there is a compensatory increase in PTH and bone resorption, leading to increased alkaline phosphatase levels. REFERENCES: Brinker MR: Cellular and molecular biology, immunology, and genetics in orthopaedics, in Miller MD (ed): Review of Orthopaedics, ed 3. Philadelphia, PA, WB Saunders, 2001, pp 81-94. Pettifor J: Nutritional and drug-induced rickets and osteomalacia, in Farrus MJ (ed): Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, ed 5. Philadelphia, PA, Lippincott Williams and Wilkins, 2003, pp 399-466. Einhorn TA: Metabolic bone disease, in Einhorn TA, O'Keefe RJ, Buckwalter JA (eds): Orthopaedic Basic Science: Foundations of Clinical Practice, ed 3. Rosemont, IL, American Academy of Orthopaedic Surgeons, 2006, in press.