The case study

Multiple choice questions

• 1.
  

  The following is/are true concerning fragility hip fractures in men:

  
  
  
  
  • A.
    

    Are diagnostic of osteoporosis and are associated with a worse prognosis than fragility hip fractures in women.

    
    
  • B.
    

    Up to one-third of the patients die within a year of the fracture.

    
    
  • C.
    

    Less than 10% of men and 25% of women who sustain an osteoporotic fracture are treated for osteoporosis.

    
    
  • D.
    

    A and B.

    
    
  • E.
    

    A, B, and C.

  
  
  
  

  Correct answer: E

  
  

  Comments:

  
  

  Fragility fractures, i.e., fractures occurring in the absence of trauma (atraumatic fractures) or as a result of trauma that ordinarily would not be expected to give rise to a fracture (low trauma or low impact fractures), are diagnostic of osteoporosis.

  
  

  It is estimated that one in four men over the age of 50 years is expected to sustain an osteoporotic fracture, and approximately half of the female population over the age of 50 years is expected to sustain a fragility fracture. Hip fractures are life-changing events. The mortality and morbidity associated with hip fractures are worse in men than in women: about one-third die within 1 year of the fracture. Osteoporosis, particularly in men, remains underdiagnosed and undertreated: less than 10% of men who have sustained a hip fracture are treated for osteoporosis. Several guidelines have been published to help identify and treat these patients.

  
  

  Osteoporosis, nevertheless, still remains an asymptomatic, silent disease and often patients who have sustained a fragility fracture deny having a diagnosis of “Osteoporosis”: “ I just fractured my hip…. It’s only a fracture; I do not have osteoporosis” are frequent comments made by patients and often reinforced by the lack of urgency from the patient’s health care providers. As already mentioned, a fragility fracture is diagnostic of osteoporosis on par with, for instance, ketoacidosis being diagnostic of diabetes mellitus. No health care provider would manage a patient’s ketoacidosis and ignore the underlying diagnosis of diabetes mellitus. The same should apply to fragility fractures, which are often the first manifestation of the underlying problem: osteoporosis, hence the remark that “osteoporosis is a silent disease” albeit until a fragility fracture occurs. Osteoporosis in men is discussed in another case study in this series.

  
  
• 2.
  

  Factors affecting outcome after sustaining a fragility hip fracture include:

  
  
  
  
  • A.
    

    Prefracture level of cognitive functioning.

    
    
  • B.
    

    Prefracture level of physical independence.

    
    
  • C.
    

    Comorbidities prior to the fracture.

    
    
  • D.
    

    A, B, and C.

    
    
  • E.
    

    B and C.

  
  
  
  

  Correct answer: D

  
  

  Comment:

  
  

  The level of cognitive functioning prior to sustaining the fracture is the single most important prognostic factor for resuming prefracture function. The level of physical independence and prefracture comorbidities also affect the prognosis. The longer the period of physical inactivity after sustaining a fracture, the more likely are the skeletal muscles to waste, and atrophy, leading to instability, weakness, increased risk of further falls and fractures. Physical rehabilitation should start as soon as possible after surgical fracture repair. Patients’ motivation for return to their own environment should be kept high.

  
  
• 3.
  

  When administered within 90 days after a hip fracture, compared to placebo, over a 2-year period, annual Zoledronic acid (ZA) intravenous infusions reduced:

  
  
  
  
  • A.
    

    Clinical fractures by 35%.

    
    
  • B.
    

    Vertebral fractures by 46%.

    
    
  • C.
    

    Overall mortality by 28%.

    
    
  • D.
    

    A and C.

    
    
  • E.
    

    A, B, and C.

  
  
  
  

  Correct answer: E

  
  

  Comment:

  
  

  These are the results of the “ H ealth O utcomes and R educed I ncidence with Z oledronic acid On ce yearly— P ivotal F racture T rial: HORIZON—PFT .” It is an international, randomized, double-blind, placebo controlled, clinical trial on men and women who sustained a hip fracture and underwent surgical repair in the 90 days prior to enrollment in the study. A subsequent analysis demonstrated the positive effects of ZA when administered as early as 2 weeks after the fracture occurred.

  
  
• 4.
  

  The likelihood of the patient being diagnosed and treated for osteoporosis after sustaining a fragility fracture is:

  
  
  
  
  • A.
    

    60%.

    
    
  • B.
    

    50%.

    
    
  • C.
    

    45%.

    
    
  • D.
    

    33%.

    
    
  • E.
    

    25%.

  
  
  
  

  Correct answer: E

  
  

  Comment:

  
  

  It is difficult to rationalize how it is possible that only one of every four patients who sustain an osteoporotic fragility fracture is diagnosed and treated for osteoporosis, even though it is well established that fragility fractures, per se, are diagnostic of osteoporosis. Furthermore, once an osteoporotic fracture has occurred, the risk of sustaining further fractures is substantially increased and the morbidity and mortality after sustaining an osteoporotic fracture are also significantly increased. The irony is that we now have effective, relatively safe, and cheap medications that can reduce the risk of vertebral, nonvertebral, and even hip fractures.

  
  
• 5.
  

  Following a fragility osteoporotic fracture, the risk of sustaining, within 18 months, a subsequent hip fracture is approximately:

  
  
  
  
  • A.
    

    72.5%.

    
    
  • B.
    

    64%.

    
    
  • C.
    

    56%.

    
    
  • D.
    

    43%.

    
    
  • E.
    

    28%.

  
  
  
  

  Correct answer: E

  
  

  Comment:

  
  

  A large retrospective cohort study which included 115,776 patients, 65 years of age and older, who sustained a hip fracture, revealed that a subsequent second hip fracture occurred in 27.8% of the patients who sustained a hip fracture. The median time to a second hip fracture was approximately 18 months postindex event. The one-year mortality rate from any cause after the index hip fracture was 26.2%. There is a need to recognize that at present a number of medications are commercially available to significantly reduce the risk of further fractures, including hip fractures. The judicious use of these medications should ensure maximal benefit and minimal adverse effects.

  
  
• 6.
  

  Zoledronic acid (ZA) is effective for the:

  
  
  
  
  • A.
    

    Treatment and prevention of postmenopausal osteoporosis.

    
    
  • B.
    

    Treatment and prevention of glucocorticoid-induced osteoporosis.

    
    
  • C.
    

    Treatment of men with osteoporosis.

    
    
  • D.
    

    A, B, and C.

    
    
  • E.
    

    A and B.

  
  
  
  

  Correct answer: D

  
  

  Comments:

  
  

  ZA is useful for the management of the previously mentioned conditions. At the end of 3 years, compared to placebo, ZA infusions reduced hip fractures by 41%, morphometric vertebral fractures by 70%, and clinical vertebral fractures by 77% in postmenopausal women with osteoporosis. It is also effective in postmenopausal women with osteopenia and men with osteoporosis and osteopenia. ZA is also useful for the prevention and treatment of osteoporosis in patients on glucocorticoids, patients on aromatase inhibitors those with metastatic bone disease, those with HIV-induced bone loss, and to prevent poststroke bone demineralization.

  
  
• 7.
  

  Zoledronic acid (ZA):

  
  
  
  
  • A.
    

    ZA is an intravenously administered bisphosphonate.

    
    
  • B.
    

    Overcomes issues related to adherence with oral bisphosphonates.

    
    
  • C.
    

    Should not be administered if the creatinine clearance is 35 mL/min or less.

    
    
  • D.
    

    Should not be administered to patients with hypocalcemia.

    
    
  • E.
    

    All of the above.

  
  
  
  

  Correct answer: E

  
  

  Comments:

  
  

  ZA is a bisphosphonate administered once a year by intravenous infusion. It overcomes many issues related to adherence (compliance and persistence) to oral bisphosphonate therapy.

  
  

  AJ is a good candidate for ZA: he could tolerate neither alendronate, nor risedronate, nor ibandronate, and his travel schedule is such that adherence to oral bisphosphonates is likely to be low. Denosumab is another alternative, discussed in another case study.

  
  

  As ZA is excreted by the kidneys, its administration is not recommended to patients with a creatinine clearance of 35 mL/min or less and caution should be exercised when administered with potentially nephrotoxic medications, including, and especially, nonsteroidal antiinflammatory medications as they can be obtained over the counter, without a medical prescription. Transient elevations in serum creatinine levels were observed in 1.3% of patients receiving ZA infusion as opposed to 0.4% of those receiving placebo infusions. However, within 30 days of the infusion the serum creatinine levels returned to the preinfusion levels.

  
  

  Hypocalcemia may occur in patients who rely on the mobilization of calcium from the skeleton to the circulatory compartment to maintain the serum calcium level within a narrow range. By suddenly inhibiting bone resorption, ZA may reduce calcium flow from bones to circulation, thus inducing hypocalcemia or aggravating an existing one. ZA should not be administered to patients with hypocalcemia.

  
  
• 8.
  

  The Acute Phase Reaction (APR) following ZA iv infusion:

  
  
  
  
  • A.
    

    Affects about 18% of bisphosphonate naïve patients, but only about 9% of patients previously exposed to bisphosphonates.

    
    
  • B.
    

    Presents as fatigue, headaches, generalized aches and pains, myalgia, bone/joint pains, and low-grade fever.

    
    
  • C.
    

    Is significantly reduced if the patient takes acetaminophen 1000 mg or a nonsteroidal antiinflammatory drug before the infusion.

    
    
  • D.
    

    Is an allergic reaction.

    
    
  • E.
    

    A, B, and C.

  
  
  
  

  Correct answer: E

  
  

  Comments:

  
  

  The APR is probably the result of a large bisphosphonate dose administered over a short period of time (15–30 min). It is also seen, albeit to a much lesser extent, when oral monthly doses of bisphosphonates are taken for the first time. Patients with the APR experience a variety of symptoms, including generalized aches or pains, low-grade fever, malaise, and fatigue occurring 1 or 2 days after the infusion and lasting 3–5 days. Occasionally it may last longer.

  
  

  The APR is seen more frequently in bisphosphonate naïve patients than in those who had been on oral bisphosphonates and is less frequent and less severe after the second and subsequent infusions. It is not an allergic reaction. The incidence and severity are reduced by the intake of acetaminophen before the infusion. Although nonsteroidal antiinflammatory medications also reduce its severity, they should be used cautiously given their potential nephrotoxicity.

  
  
• 9.
  

  The musculoskeletal pain experienced after the administration of ZA:

  
  
  
  
  • A.
    

    Is usually localized to the lower back, hips, upper legs, and occasionally ribs.

    
    
  • B.
    

    Is part of the acute phase reaction.

    
    
  • C.
    

    Usually occurs within hours of the ZA administration.

    
    
  • D.
    

    Is usually relieved spontaneously within a few days of the ZA administration.

    
    
  • E.
    

    A, C, and D.

  
  
  
  

  Correct answer: A

  
  

  Comment:

  
  

  Patients may develop moderate to severe pain in the lower back, hips, upper thighs, and occasionally ribs after the intravenous or oral administration of bisphosphonates. Unlike the APR which occurs within a few days of ZA administration, musculoskeletal pains occur any time. The underlying mechanism of musculoskeletal pain postadministration of bisphosphonates is poorly understood. It can be related to hypovitaminosis D and compensatory secondary hyperparathyroidism associated with an increased bone turnover rate and bone vascularity resulting in a higher concentration of bisphosphonate in the bone microenvironment leading to increased production of proinflammatory cytokines and triggering a localized inflammatory response. There is also some evidence to suggest that patients who develop an APR have a better BMD response than those who do not experience it.

  
  
• 10.
  

  Adverse effect(s) reported after ZA administration include:

  
  
  
  
  • A.
    

    Arrhythmias.

    
    
  • B.
    

    Atrial fibrillation.

    
    
  • C.
    

    Myocardial infarction.

    
    
  • D.
    

    A and B.

    
    
  • E.
    

    All of the above.

  
  
  
  

  Correct answer: E

  
  

  Comment:

  
  

  Atrial fibrillation occurred in 6.9% of the patients on ZA as opposed to 5.3% of the patients on placebo. The onset of arrhythmias typically was more than 30 days after ZA iv infusion, casting doubt on a cause-and-effect relationship.

  
  

  Very rarely, diffuse, severe, unilateral ocular and orbital inflammation including corneal endotheliitis, anterior uveitis, and scleritis has been reported within 12 h of the zoledronic acid intravenous infusion. Topical steroids, and high-dose systemic corticosteroids as well as referral to expert opinion, may be recommended.

Case summary