Learning objectives
Osteoporosis in men, as in women, is asymptomatic until a fracture occurs. It is very often underrecognized, underdiagnosed, and undertreated.
Osteoporosis is less frequent in men than in women, but its mortality and morbidity impact is worse in men.
- •
In men, osteoporosis tends to manifest itself about a decade later than women.
- •
As in women, once an osteoporotic fracture is sustained, the risk of sustaining further fractures is increased.
- •
With the exception of testosterone and estrogen, essentially the same medications used to treat osteoporosis in women can be used to treat men.
- •
In men, as in women, for best results, the pharmacologic management should be complemented by lifestyle changes and an adequate diet.
The case study
Reasons for seeking medical help
- •
JB, 71 years old, watched a documentary on falls and fractures in older people and is concerned he may have osteoporosis.
- •
He is asymptomatic; cognitively intact; physically independent; lives on his own; drives his own car; travels extensively; and denies dizzy spells, falls, or near-falls.
Past medical/surgical history
- •
Hyperlipidemia, well controlled.
Personal habits, lifestyle, daily routine
- •
JB is a retired school teacher but continues to be involved teaching English literature.
- •
He lives on his own and leads a sedentary lifestyle.
- •
Average daily caffeine intake: four cups, about 16 oz each cup.
- •
Daily calcium intake: average 1000 mg.
- •
Alcohol intake: at least two drinks every day, usually more during the weekend.
- •
Cigarette smoking: about 10 cigarettes a day, used to smoke more, plans to stop it altogether.
- •
Enjoys pickles, crisps, and salty food.
Medications
- •
Simvastatin 40 mg daily.
- •
Multivitamin tablets once a day.
- •
Over-the-counter sleep aids: on an as needed basis, not exceeding one tablet a week.
Family history
- •
Negative for osteoporosis.
Clinical examination
- •
Weight 186 pounds, steady, height 62.75″, used to be 66.5″.
- •
Mild kyphosis.
- •
No clinical signs suggesting an increased falls and fracture risk:
- ○
Sitting BP 136/85, standing BP 142/86, no orthostasis.
- ○
No clinical evidence of carotid stenosis, carotid sinus sensitivity, vertebrobasilar insufficiency.
- ○
No clinical evidence of fluid retention, heart failure, or pulmonary congestion.
- ○
No localizing neurological signs.
- ○
- •
No other significant clinical findings.
Laboratory investigations
- •
Comprehensive metabolic profile: no abnormal finding.
- •
Serum 25-hydroxy-vitamin D: 42 ng/mL.
DXA scan results
- •
T-scores: right femoral neck: −1.9, right total hip: −1.4, distal 1/3 radius: −1.3; L1–L4: cannot be reliably interpreted because of osteophytes.
Vertebral fracture assessment: moderate wedge compression fractures of T7 (29.2%) and T8 (26.6%). He denies any history of back trauma or injury or pain.
- •
FRAX score (with BMD): hip fracture: 3.7%; major osteoporotic fractures: 22%.
Multiple choice questions
- 1.
In JB’s case the final diagnosis is:
- A.
Osteoporosis.
- B.
Osteopenia.
- C.
Morphometric vertebral compression fractures.
- D.
A and C.
- E.
B and C.
Correct answer: D
Comments:
As mentioned earlier, osteoporosis in men is silent until a fracture occurs. It is underdiagnosed, undertreated, and associated with a worse prognosis than in women. Also, when compared to women, more men have secondary osteoporosis. A detailed medical history, thorough clinical examination, and laboratory profile are therefore recommended prior to initiating therapy. As in women, the presence of vertebral compression fractures in the absence of significant trauma is, per se, characteristic of fragility fractures and establishes the diagnosis of osteoporosis, even if the BMD is not within the osteoporotic range.
The indications for initiating pharmacologic treatment in men are the same as in women based on the following :
- •
Clinical diagnosis: the presence of fragility fracture(s), including morphometric (i.e. silent), vertebral compression fractures.
- •
Densitometric diagnosis : lowest T-score in femoral neck, total hip, lumbar vertebrae, or distal 1/3 radius: −2.5 or lower.
- •
Increased fracture risk: estimated by the 10-year probability of sustaining a hip fracture of 3% or more, or a major osteoporotic fracture of 20% or more, as determined by the FRAX algorithm and the threshold suggested by the National Osteoporosis Foundation.
- A.
- 2.
At this stage, in JB’s case, the following serum assays are recommended:
- A.
Parathyroid hormone.
- B.
1,25-Di-hydroxy-vitamin D.
- C.
Testosterone.
- D.
Estradiol.
- E.
None of the above.
Correct answer: E
Comment:
None of these tests are necessary at this stage. Unless secondary hyperparathyroidism is suspected, there is no need to assay the serum parathyroid hormone level because the serum calcium level is within the normal range. Similarly, there is no need to assay the serum 1,25-di-hydroxy-vitamin D because it only reflects the ability of the parathyroid hormone to hydroxylate, in the kidneys, 25-hydroxy-vitamin D at the 1-position to produce 1,25-di-hydroxy-vitamin D which is the most active vitamin D metabolite produced when the serum calcium is about to fall. 1,25-di-hydroxy-vitamin D does not accurately reflect the overall vitamin D status and has a short half-life.
The preferred assay to determine vitamin D status is the 25-hydroxy-vitamin D assay, which includes 25-hydroxy-cholecalciferol and 25-hydroxy-ergocalciferol. The former is the result of the action of UV violet light, including sunlight, on the skin, and the intake of food rich in vitamin D: cholecalciferol or ergocalciferol. The latter (ergocalciferol) is derived from plants. Both cholecalciferol and ergocalciferol are metabolized through the same pathways.
Whether or not to routinely assay the serum testosterone level is debatable. It is likely to be low because of the expected age-related hypogonadism: andropause, similar to the menopause in women, albeit occurring about a decade or more, later than in women. Confirmation of low testosterone levels also will not affect the osteoporosis treatment strategy, because other medications, apart from testosterone, are effective at increasing bone mass and reducing the risk of fractures in men.
Furthermore, the administration of testosterone is associated with a number of adverse effects, including polycythemia, sleep apnea, benign prostate hypertrophy, and unmasking of prostate cancer. These adverse reactions outweigh the potential benefits of testosterone if used for the management of osteoporosis.
There is also a paucity of studies on the effects of testosterone in the management of osteoporosis in men with fractures as an end point. In one placebo-controlled, double-blind study, the investigators randomly allocated 295 men, 65 years of age and older, with hypogonadism, as evidenced by two morning serum testosterone levels averaging less than 275 ng/dL, to either a testosterone gel or a placebo. One hundred and eighty-nine participants completed the one-year study.
At the end of this period, men allocated to receive testosterone gel, compared to those receiving placebo, showed significantly greater increases in mean spine trabecular, spine peripheral, hip trabecular, and peripheral volumetric BMD (vBMD) as determined by quantitative computed tomography. These increases were paralleled by increases in the mean estimated strength, as determined by finite element analysis of quantitative computed tomography at these bone sites, were more pronounced in trabecular than peripheral bone, and more in the spine than in the hip. As expected, the median serum concentrations of total testosterone, free testosterone, and estradiol increased in the testosterone gel group to within the normal ranges for young men. Changes in aerial BMD (aBMD) as assessed by bone densitometry (DXA) were much less than those seen by vBMD. At present, these results must be tempered by the relative lack of long-term studies and the potential adverse effects associated with testosterone therapy in older men.
The serum estradiol level and sex hormone binding globulin (SHBG) are major factors affecting bone loss in older men. It has been suggested that whereas estrogen reduces the fracture risk by direct effects on bones, androgens in addition affect muscle bulk and may reduce the risk of falls and hence fractures. The Endocrine Society Clinical Practice Guidelines emphasize that the diagnosis of hypogonadism be made only in men with symptoms and signs of testosterone deficiency and unequivocally and consistently low serum testosterone levels.
- A.
- 3.
In JB’s case, the following medications are recommended as a first choice:
- A.
Bisphosphonates, teriparatide, abaloparatide, denosumab, romosozumab, raloxifene, or calcitonin.
- B.
Bisphosphonates, teriparatide, abaloparatide, denosumab, or romosozumab.
- C.
Bisphosphonates, teriparatide, abaloparatide, or denosumab.
- D.
Bisphosphonates or denosumab.
- E.
Bisphosphonates.
Correct answer: D
Comments:
Most studies on the treatment of osteoporosis in men are much smaller than those conducted on postmenopausal women and with few exceptions, most do not have fractures as an end point. It is assumed that if the changes in BMD and bone turnover rates are similar to those observed in women then the effect on fracture risk is similar. Therefore, as in this patient the hip fracture risk is elevated, medications that have been shown to effectively reduce the risk of hip fractures should be the first choice. Neither raloxifene nor calcitonin has been shown to be effective at reducing the risk of hip fractures.
Teriparatide, abaloparatide, and romosozumab are osteoanabolic agents and have been shown to reduce the risk of fractures, including hip fractures. They are, however, not often used as first line of therapy for the management of osteoporosis because of their need to be administered parenterally and their cost. Up till recently the administration of teriparatide and abaloparatide was limited to 2 years because there was uncertainty about its possible carcinogenicity, as per findings of a study conducted on experimental rats. That restriction of 2 years for both teriparatide and abaloparatide has now been lifted. These medications are discussed in other sections.
Bisphosphonates and denosumab have been shown to be effective in the management of osteoporosis in men either as monotherapy, consolidative therapy after a course of teriparatide/abaloparatide, or in combination with testosterone replacement therapy in men with osteoporosis secondary to hypogonadism.
- A.
- 4.
The following are also recommended in this patient:
- A.
Reducing the sodium and caffeine intake.
- B.
Calcium and vitamin supplementation.
- C.
Stop cigarette smoking.
- D.
A, B, and C.
- E.
A and C.
Correct answer: E
Comments:
Reducing sodium and caffeine intake is important as both increase the renal calcium excretion and may induce a negative calcium balance resulting in secondary hyperparathyroidism and bone demineralization. Stopping cigarette smoking is an important integral part of the management of patients with osteoporosis. Cigarette smoking predisposes to osteoporosis and increases the risk of fractures in men more than in women. The detrimental effect of cigarette smoking on bone mass during the growth period cannot be reversed once peak bone mass is reached. There is no need to supplement the calcium and vitamin D intake as JB is already getting an adequate amount of calcium through food, and his serum 25-hydroxy-vitamin D level is within the normal range.
- A.
- 5.
The following lifestyle and medication changes are recommended in JB:
- A.
Undertake regular weight-bearing physical exercise.
- B.
Reduce alcohol consumption to no more than 2 drinks a day.
- C.
Reduce and preferably discontinue use of over-the-counter sleep aids.
- D.
B and C.
- E.
A, B, and C.
Correct answer: E
Comment:
All the listed modalities are important in JB’s case. There is, however, a paucity of well-designed and well-conducted long-term studies on the effects of physical exercise and lack of physical exercise on bone mass and fracture risk in older subjects. Nevertheless, given the available evidence, it seems reasonable to assume that physical exercise, especially weight-bearing exercises, may help improve bone mineral density, muscle bulk, postural reflexes, and reduce the risk of falls and fractures. The US Endocrine Society recommends weight-bearing activities for 30–40 min three to four times a week. Lifting free weights, however, has a potential for physical injury. Similarly, high-resistance exercises may detrimentally affect neighboring joints especially in patients with arthropathies. Intuitively, supervised physical exercise programs should yield better results than nonsupervised ones, as it is possible to target and fine-tune exercise programs geared to the individual circumstances and needs of the patient.
Excessive alcohol intake is associated with bone demineralization, falls, and fractures. With an alcohol consumption of more than 3 units a day, the relative hazard of hip fracture is almost double (RH 1.92, 95% CI 1.28–2.88) and for all fractures is 1.32 (95% CI 1.10–1.60). Often, however, self-reported alcohol usage underestimates the true alcohol consumption.
Hypnotics, especially sleep aids available over the counter, increase the risk of unsteadiness, confusion, falls, and fractures and their effect is potentiated by the consumption of alcoholic beverages.
- A.
- 6.
The following is/are true:
- A.
About a third of hip fractures occur in men.
- B.
Posthip fracture mortality in men is much higher than in women.
- C.
Most men who sustain fragility fracture also have a densitometric diagnosis of osteoporosis.
- D.
A and B.
- E.
A, B, and C.
Correct answer: D
Comment:
Osteoporosis in men remains underrecognized, underdiagnosed, and undertreated. About a quarter of hip fractures occur in men. The risk of sustaining a fragility fracture for men aged 50 and older is 13%–30%. Fragility fractures are, nevertheless, less frequent in men than in women for a variety of reasons, including that men tend to have larger bones than women, fall less frequently than women, and their life expectancy is shorter than in women. Notwithstanding, subsequent to a fragility hip fracture, mortality is two to three times higher in men than in women.
Only about 20% of men who sustain a fragility hip or major osteoporotic fracture have a densitometric diagnosis of osteoporosis. This could be due to changes in bone microarchitecture and increased cortical porosity which are not captured by DXA scans, hence the need for an assessment of the patient’s fracture risk.
There is also some controversy concerning the reference population used for the densitometric diagnosis of osteoporosis in men. Whereas the International Osteoporosis Foundation recommends using a Caucasian female reference population to calculate the T-scores, the National Osteoporosis Foundation recommends a male reference population be used for this purpose and the International Society for Clinical Densitometry leaves it to the individual center to decide which reference population to use.
The justification of using a female Caucasian reference population is that the risk of fracture is dependent on the bone’s absolute BMD regardless of the patient’s gender and ethnic group. This, nevertheless, may create problems when interpreting follow-up DXA scans done in different centers without knowing which reference population has been used to calculate the T-scores.
It also has important implications: if a female reference population is used to calculate the T-scores of a male patient, fewer patients will be diagnosed and hence treated for osteoporosis. On the other hand if a male reference population is used, more patients will be diagnosed with osteoporosis and may be unnecessarily treated.
- A.
- 7.
Men over the age of 50 years should be screened for osteoporosis if:
- A.
They have sustained a fragility fracture.
- B.
They had a delayed puberty.
- C.
They have evidence of hypogonadism.
- D.
B or C.
- E.
A, B, or C.
Correct answer: E
Comment:
It is estimated that one-third of fragility fractures occur in men and 20% of patients with osteoporosis or low bone mass are men.
In men, as in women, a fragility fracture is diagnostic of osteoporosis. Therefore, although there is no need to screen these patients to diagnose osteoporosis, a DXA scan is still needed, not for diagnostic purposes, but to establish a baseline against which the patient’s progress or lack thereof can be monitored.
Following a hip fracture, the mortality, morbidity, and loss of independence are more pronounced in men than in women. Factors increasing the risk of sustaining a fall complicated by a hip or other bone fracture include: age: 70 years and older, low body weight, excessive alcohol consumption, impaired visual acuity, frailty, inability to perform daily activities, and low BMD.
Repeated falls and fractures are also more likely to occur in patients who smoke cigarettes, have already sustained a fracture, experience falls or near-falls, have cataracts, impaired vision, cognitive impairment, or have been diagnosed with a number of medical conditions, including arrhythmias (especially atrial fibrillation, bradycardia, tachycardia, and tachy-bradycardia), hypertension, orthostatic hypotension, congestive cardiac failure, chronic obstructive pulmonary disease, diabetes mellitus, hypo/hyperthyroidism, myocardial infarction, Parkinson’s disease, peripheral neuropathy, rheumatoid arthritis, strokes, and transient ischemic attacks. Reduced physical activity also increases the risk of sustaining a hip fracture by inducing muscle atrophy and sarcopenia.
A number of medications may predispose to falls and fractures, including benzodiazepines, antidepressants, anticonvulsants, psychotropics, beta-blockers, hypotensives, and hypnotics, including those available over the counter as they are likely to induce drowsiness, interfere with cognitive functions, and tend to have a long half-life.
The consensus is to screen men aged 70 years and older regardless of whether or not they have risk factors for osteoporosis and to screen men 50 years and older if they have risk factors for osteoporosis, including delayed puberty, hypogonadism, and hyperthyroidism. Similarly, it is relevant to screen for osteoporosis in men taking medication that may increase the risk of falling as well as those whose lifestyle predisposes to bone demineralization such as cigarette smoking, sedentary lifestyles, and excessive sodium and caffeine intake.
Given the prevalence of osteoporosis in men, its prognosis, and silent nature until a fracture occurs, it has been suggested that screening for osteoporosis in men start at a younger age: 60 instead of 70 years.
- A.
- 8.
When assessing falls and fracture risks in men:
- A.
A thorough clinical examination is essential to identify the cause(s) of repeated falls.
- B.
The Fracture Risk Assessment algorithm (FRAX) algorithm cannot be used in men.
- C.
The Garvan Fracture Risk Calculator cannot be used in men.
- D.
A and B.
- E.
A, B, and C.
Correct answer: A
Comment:
Assessing fracture risk is important to develop a comprehensive management strategy tailored to the individual circumstances of the patient which includes nonpharmacologic modalities and lifestyle modifications. Both the FRAX tool and the Garvan Fracture Risk Calculator can be used in men, although it has been suggested that FRAX underestimates the fracture risk in men. The FRAX score, calculated without BMD, does not correctly identify men with densitometric evidence of osteoporosis.
- A.
- 9.
In aging men:
- A.
Free estrogen rather than free testosterone levels correlates best with the BMD.
- B.
Sex Hormone Binding Globulin (SHBG) levels increase.
- C.
Free testosterone levels decrease.
- D.
B and C.
- E.
A, B, and C.
Correct answer: E
Comment:
In aging men, the decreases of serum testosterone (and estrogen) levels are more gradual and due to a more than twofold increase in Sex Hormone Binding Globulin which reduces the bioavailability of free testosterone and estrogen in older men by 64% and 47%, respectively. In men, free estrogen rather than free testosterone levels correlates best with the BMD. Testosterone also may reduce the fracture risk through its positive effect on balance, muscle bulk, and strength.
- A.
- 10.
In men with prostate cancer on androgen deprivation therapy:
- A.
Lumbar vertebrae BMD decreases by about 4% in the first year of therapy.
- B.
Hip BMD decreases by about 6% in the first year of therapy.
- C.
Fracture risk is increased.
- D.
A and C.
- E.
A, B, and C.
Correct answer: D
Comment:
Decreases of 3%–4% in lumbar vertebrae BMD have been reported during the first year of androgen deprivation therapy in men with prostate cancer. The decreases in hip BMD are less pronounced, but the fracture risk is increased in this population. Several medications have been shown to be effective to reduce bone loss in men on androgen deprivation therapy, including alendronate, zoledronic acid, pamidronate, denosumab, and raloxifene. Over a 36-month period denosumab decreased the risk of vertebral fractures by 62% in men on androgen deprivation therapy.
- A.
Case summary
Analysis of data
Factors predisposing to bone demineralization/osteoporosis
- •
Patient’s age: 71 years.
- •
Sedentary lifestyle.
- •
High caffeine intake.
- •
Excessive alcohol intake.
- •
Cigarette smoking.
- •
High sodium intake (pickles, crisps, and salty food).
Factors reducing the risk of bone demineralization/osteoporosis
- •
Negative family history for osteoporosis.
- •
Good intake of vitamin D and calcium.
Factors increasing the risk of falls/fractures
- •
Over-the-counter sleep aids.
Factors reducing the risk of falls/fractures
- •
Physically active lifestyle.
Bone health diagnosis
- •
Osteoporosis, as evidenced by presence of fragility vertebral compression fractures of T7 and T8.
- •
Increased fracture risk as per FRAX: 10-year probability of sustaining a hip (3.7%) or major fracture (22%) exceeding National Osteoporosis Foundation threshold to initiate pharmacologic treatment.
Management recommendations
Further diagnostic tests
- •
None needed at present.
Treatment recommendations
Medications
- •
Bisphosphonates or denosumab.
Physical therapy/lifestyle changes
- •
Combination of aerobic and resistive exercises.
- •
Reduce sodium and caffeine intake.
- •
Stop cigarette smoking.
- •
Adopt a physically active lifestyle.
Follow-up
Outpatient clinic or telehealth encounter 4 to 6 weeks after initiating therapy:
- •
If the patient elected to go on oral bisphosphonate therapy this visit can be used to ensure the medication is taken exactly as directed, that no adverse effects developed, and that the patient is happy to continue taking the bisphosphonate. This also offers an opportunity to emphasize the importance of the recommended dietary and lifestyle changes including getting involved in a regular, preferably supervised, physical exercise program.
- •
If the patient elected to receive parenteral bisphosphonates or denosumab: an outpatient visit, 4–8 weeks later, to address any concern the patient may have and emphasize the importance of the recommended dietary and lifestyle changes including getting involved in a regular, preferably supervised, physical exercise program. In addition, if the patient decided to go on denosumab, this visit could be used to emphasize the importance of receiving the medication on the scheduled 6-month visit and of the risks involved should the next dose be postponed.
- •
Regardless, this follow-up visit is an opportunity to emphasize to the patient the seriousness of osteoporosis and the potentially good results anticipated provided the medication is taken regularly and exactly as directed.
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