Osteoporosis in Men: Overview of an Underrecognized and Undertreated Problem

ABSTRACT: Historically, osteoporosis has been a condition most often associated with women. Osteoporosis in men, however, is a critical problem that is often overlooked. In fact, many men remain unaware that they have osteoporosis until they experience a skeletal-related event, and many physicians do not think to screen their male patients for this disease. This article provides an overview of osteoporosis in the male population, reviewing its classification, etiology, risk factors, diagnosis, and treatment.

The National Osteoporosis Foundation (NOF) estimates that 2 million American men have osteoporosis and that 12 million more are at risk of developing the disease.¹ In addition, it has been reported that between 3% and 6% of US men have osteoporosis in the hip, while 28% to 47% have osteopenia, which is considered a precursor to osteoporosis.² Osteoporosis increases the risk of fracture, and 1 in 8 men older than 50 years is projected to experience an osteoporosis-related fracture during his lifetime.³ 

Diagnostically, osteoporosis is characterized by low bone mass, microarchitectural deterioration of bone tissue, and an increase in bone fragility, which collectively increase the susceptibility to fracture.³ These changes, particularly early in the disease process, do not produce symptoms; thus, osteoporosis is commonly referred to as the silent disease.⁴ Generally, only when a fracture occurs does the disease manifest itself and come to the attention of healthcare providers³; however, even in such cases, when the patient is a man, he may not be screened for or receive any osteoporosis treatment. In 2008, Papaioannou et al reported the results of their 5-year study, which revealed that an overwhelming 90% of men who had sustained a fragility fracture did not receive osteoporosis screening or treatment.⁵ One reason why osteoporosis in men is commonly overlooked is because osteoporosis-induced fractures generally occur 10 years later in men than in women. Nevertheless, one-third of all hip fractures occur in men, and they are less likely than women to survive the injury or to regain mobility^..⁶ Hip and vertebral fractures are linked with increased morbidity and mortality in men sustaining these injuries.³ According to the NOF, by 2050, the worldwide incidence of hip fractures in men is projected to increase 310%.¹

Although healthcare providers have begun to recognize osteoporosis as an important condition affecting the male population, it still remains underrecognized and undertreated. This is likely because most osteoporosis research and literature has focused on women. Further, until recently, clinical guidelines regarding osteoporosis in men were lacking⁷; thus, managing skeletal health in these patients has been a challenge. In 2008, the American College of Physicians identified osteoporosis as an underrecognized and undertreated disease in men and issued guidelines for the assessment of risk factors and appropriate use of screening tools to assist in the diagnosis of osteoporosis in this population.⁸ Then in 2012, the Endocrine Society published similar guidelines regarding the management of osteoporosis in men.⁹ However, it seems that general awareness of the availability of these guidelines is still lacking in clinical practice. 

The identification and treatment of osteoporosis in men will lead to fewer fractures and improved morbidity, mortality, and quality of life for this patient population. It will also reduce the financial burden of osteoporosis, which is substantial at an estimated 17 to 20 billion dollars of annual direct medical costs in the United States alone.¹⁰

This article provides an overview of osteoporosis in men, focusing on the classification, risk factors, diagnosis, prevention, and treatment options available. By increasing awareness of this condition in the male population, outcomes can be significantly improved for these patients.

OSTEOPOROSIS CLASSIFICATIONS 

There are 4 classifications of osteoporosis: primary, secondary, osteogenesis imperfecta, and juvenile osteoporosis. 

• Primary osteoporosis. This is the most common form of osteoporosis and occurs as a direct result of aging. It is classified as type I or II. Type I is commonly referred to as postmenopausal osteoporosis, as estrogen deficiency is thought to underlie this condition. The incidence of primary type I osteoporosis is reported to be 8 times higher in women than in men.¹¹ Type II is sometimes referred to as senile osteoporosis. It occurs in persons older than 70 years and is usually associated with decreased bone formation and vitamin D and calcium deficiency. It has a female-to-male ratio of 2:1.¹¹ 

• Secondary osteoporosis. This is another common form of osteoporosis and occurs as a result of having other medical conditions, such as hyperparathyroidism, diabetes, prostate cancer, HIV, or chronic liver and kidney disease.¹² It can also result from certain medications that are known to cause bone breakdown (eg, androgen deprivation therapy [ADT], long-term use of oral or high-dose inhaled corticosteroids). In general, men are more likely than women to develop secondary osteoporosis.¹³

• Osteogenesis imperfecta. This is a rare congenital form of osteoporosis that is characterized by bones that break easily, often with little or no apparent cause.¹⁴ Although there are 4 recognized types of osteogenesis imperfecta (type I-type IV), the characteristic features of this condition vary considerably between people, even among those classified as having the same type. It is estimated that between 20,000 to 50,000 individuals in the United States have this condition, which occurs with equal frequency between the sexes.¹⁴

• Juvenile osteoporosis. This is another rare form of osteoporosis, but one with an unclear etiology.¹⁵ It generally manifests in children between the ages of 7 and 13 years, often causing pain in the lower back, hips, and feet, which is accompanied by difficulty walking. Some patients may also experience physical malformations, such as kyphosis. Although patients with juvenile osteoporosis are at an increased risk of fractures, unlike other forms of osteoporosis, this condition typically spontaneously remits and most children experience complete bone recovery.¹⁵ 

In addition to these forms of osteoporosis, osteopenia is considered by many to be “pre-osteoporosis.” It is characterized by decreased bone mineral density (BMD) that is not yet low enough to be considered osteoporosis. To distinguish between these conditions, the World Health Organization (WHO) set cutoff levels for them based on the normal values of BMD in young adults, as measured by dual-energy x-ray absorptiometry (DXA) at several designated sites of the proximal femur.^3,16 Based on these values, the WHO considers osteopenia as a BMD between 1 and 2.5 standard deviations below the normal reference values and osteoporosis as a BMD value of more than 2.5 standard deviations below the normal reference values.^3,16

ETIOLOGY OF OSTEOPOROSIS IN MEN 

In general, people reach peak bone density between the ages of 25 and 30 years,. Thereafter, bone loss slowly increases while the rate of bone building decreases.¹⁷ Estrogen is necessary for bone strength in both men and women, and when there is a loss of estrogen, osteoporosis develops. The time period when this occurs in women is more clearly defined than for men, as it typically occurs around the time of menopause. In men, bone thinning starts to occur when they lose estradiol, a metabolite of testosterone, which may start between 45 to 50 years of age when men’s testosterone levels are in decline. This loss in estradiol increases osteoclastic resorption and ultimately leads to osteoporosis.¹³ 

Throughout life, the bones constantly remodel, enabling them to adapt and change to the external environment. The integrity of the skeleton is maintained by millions of constituents called bone-remodeling units. As people age, however, there is a loss of minerals and changes in the bone matrix. It is estimated that men lose BMD at a rate of 1% per year as they age.³ Eventually, men reach the point where more bone is being resorbed than is being produced, which leads to decreased bone strength and an increased risk of fractures.¹³                      

OSTEOPOROSIS RISK FACTORS IN MEN 

A number of factors increase a man’s risk of developing osteoporosis, including:

• Age. The risk of osteoporosis increases with age, including in men. In these patients, an age of 70 years and older is considered a moderate risk factor for osteoporosis. 

• Family history. A man with a family history of osteoporosis faces an increased risk of developing osteoporosis. 

• Hormone imbalance. Testosterone deficiency is the most frequent cause of osteoporosis in men.¹³ In addition, men with lower levels of testosterone and estradiol in combination with higher levels of sex hormone binding globulin show higher rates of bone density loss over time, increasing their risk of osteoporosis.⁶ 

• Lifestyle factors. A variety of lifestyle factors can increase the risk of osteoporosis in men, including smoking, alcohol use, obesity, low body weight, weight loss, physical inactivity, and low dietary vitamin D and calcium intake.¹⁸ 

• Medical history. A number of diseases can contribute to bone loss, such as hyperthyroidism, hyperparathyroidism, hyperadrenalism, and prostate cancer. In addition, a history of fractures increases the risk of osteoporosis.

• Medication use. Many medications can contribute to bone loss, including corticosteroids (eg, prednisone), thiazolidinediones, and selective serotonin reuptake inhibitors.¹⁹ Patients receiving ADT, however, are at particularly high risk of developing osteoporosis, as this agent reduces the circulating levels of both estrogen and testosterone. This causes increased bone resorption and impaired bone formation, leading to a decrease in BMD. Studies have shown that the greatest decline in BMD (up to 10%) occurs during the patient’s first year on ADT.²⁰

DIAGNOSIS OF OSTEOPOROSIS 

Evaluation of osteoporosis begins with BMD testing using DXA scans that focus on the spine, hip, and, potentially, the forearm.⁶ Currently, BMD testing by DXA scan is the most reliable way to determine loss of bone mass. In addition, the DXA scan is painless, noninvasive, and safe. The NOF recommends BMD testing for all men older than 70 years, men aged 50 to 69 years who have the aforementioned risk factors for osteoporosis, and men with a history of fractures.¹ 

In addition, several laboratory tests may be beneficial, including measurement of 25-hydroxy vitamin D and calcium levels to determine if the patient has adequate levels of these micronutrients and measurement of testosterone levels to identify nonsymptomatic cases of hypogonadism.^1,12,16 Another helpful tool is the WHO’s Web-based Fracture Risk Assessment Tool (FRAX; available at www.shef.ac.uk/FRAX), which determines the patient’s risk of sustaining a fracture within the next 10 years by considering his or her BMD score in combination with his or her identified clinical risk factors. 

Finally, healthcare providers should be mindful that men with prostate cancer face an increased risk of osteoporosis and concomitant fractures. In fact, use of ADT has become a leading cause of osteoporosis in men, and can decrease the survival rate in a population that might otherwise live for many years with well-controlled prostate cancer. Therefore, steps should be taken to promptly diagnose the condition in these patients. It is recommended that all patients with advanced prostate cancer undergo whole-body magnetic resonance imaging so that any skeletal metastases can be identified.¹³ In addition, these patients should receive DXA scans upon initiation of ADT and annually during treatment to evaluate their bone health, enabling appropriate and timely interventions to be initiated.²¹

TREATMENT OF OSTEOPENIA AND OSTEOPOROSIS IN MEN 

Once osteopenia or primary or secondary osteoporosis is diagnosed, actions can be taken to slow and/or stop the progression of bone loss. Treatment consists of a combination of lifestyle interventions and use of pharmacological agents,³ with a goal of preserving BMD and preventing fractures. To that end, men older than 50 years or who are at high risk of osteoporosis should be advised to take the following lifestyle measures to protect their bone health: 

• Supplement their diet with 1000 mg to 1200 mg of calcium and 800 international units (IU) to 1000 IU of vitamin D daily.¹ Some patients may be inclined to take higher levels of these supplements or underestimate the amount they are receiving from their diet; thus, physicians need to explain to them that excessive vitamin D and calcium levels can cause kidney, vascular, and tissue calcifications, which would result in subsequent damage to the heart, blood vessels, and kidneys.²² 

• Engage in physical activity, including weight-bearing and muscle-strengthening exercises, to enhance bone health and improve balance.¹ However, physicians should help patients identify appropriate activities and programs, set specific and realistic goals, and discuss the individual benefits that the exercise will provide.²³                  

•Abstain from smoking. Smoking doubles the risk for osteoporosis because nicotine inhibits estrogen secretion while depleting the body of needed nutrients. Cigarette smoking contributes to 20% of hip fractures.¹³ Physicians can counsel their patients on smoking cessation and help them find an appropriate program or treatment to assist with this effort.                      

• Limit alcohol consumption. Alcohol directly damages bone cells and decreases BMD.¹³ Heavy drinkers and young drinkers are at especially high risk for bone loss. Young male patients should be advised that alcohol use is especially deleterious to growing bones, as it reduces peak bone mass, resulting in weaker adult bones that are more prone to fractures.²⁴

Although the aforementioned lifestyle choices are vital in preventing osteoporosis, these choices may not be sufficient to avert the disease. If a man has a diagnosis of osteoporosis or is at an increased risk for fractures, medication is warranted to reduce the risk of osteoporosis. Pharmacological agents for osteoporosis have been shown to be cost-effective in all populations.¹³ Although these medications do not cure osteoporosis, they can slow or even stop disease progression.¹ 

Pharmacological treatment is recommended for men older than 50 years who have had previous fractures, have an osteoporosis diagnosis, or are considered at high risk based on low BMD levels and/or their clinical risk factors.¹² In addition, men treated for hypogonadism and who have additional risk factors or testosterone levels below 200 ng/dL are candidates for pharmacological treatment.

Hormone replacement therapy (HRT). HRT is indicated if the man is symptomatic (eg, has decreased libido, lethargy, changes in mood, loss of muscle mass), has a normal digital rectal examination, and has a normal prostate-specific antigen test. HRT is contraindicated in men with breast cancer or prostate cancer. Currently, HRT consists of a number of treatment options, including topical testosterone creams or gels, intramuscular injections of testosterone cypionate, skins patches, and subcutaneous, slow-release, implanted pellets that are replaced every 4 to 6 months. Hypogonadal men who receive HRT have been shown to increase their BMD values to match those of same-aged men who do not have low testosterone levels.¹² Although HRT is generally safe, some men experience side effects such as acne, breast enlargement, worsening sleep apnea, decreased testicular size, fluid retention, urinary frequency, increased red blood cell count, and a decreased sperm count.²⁵ 

Bisphosphonates. These agents can be used as monotherapy or in combination with testosterone replacement in men with hypogonadism and osteoporosis,²⁶ and they have been used successfully for the prevention and treatment of all forms of osteoporosis. Bisphosphonates are deposited on the surface of bones, inhibiting osteoclasts and preventing bone resorption.¹³ Bisphosphonates also have a beneficial effect on osteoblasts, enabling them to form bone faster than or at the same rate as that which osteoclasts break bone down. Bisphosphonates, which can be administered orally or intravenously, are typically well tolerated. The most common side effect of oral bisphosphonates is heartburn, whereas intravenous bisphosphonates generally cause muscle soreness.²⁷ Men with prostate cancer receiving bisphosphonates may experience the more severe side effect of osteonecrosis of the jaw; thus, these patients need to receive dental clearance before initiating treatment. Optimal use of bisphosphonates for osteoporosis requires adequate intake of vitamin D and calcium before and during therapy.²⁸ 

Bisphosphonates have been shown to be as effective in men with primary osteoporosis as in men with secondary osteoporosis from nonmetastatic prostate cancer and receiving ADT.²¹ Men with metastatic prostate cancer also benefit from bisphosphonates. Zoledronic acid is an intravenous bisphosphonate that reduces the risk of bone complications, including pain and fractures, in these patients.²⁹ 

Denosumab. This agent is specifically indicated for patients who have gastrointestinal side effects from bisphosphonates or chronic renal failure, a condition that contraindicates the use of bisphosphonates. Denosumab has a different mechanism of action from bisphosphonates. It is a human monoclonal antibody that bonds to and neutralizes human receptor activator of nuclear factor kappa-B ligand (RANKL); the RANKL signaling pathway regulates the activation, differentiation, proliferation, and apoptosis of osteoclasts.³⁰ 

Denosumab has been shown to increase bone density and prevent fractures in men who develop osteoporosis as a consequence of ADT.²⁹ The most common side effects of denosumab are mild and include back and other muscular pain, skin irritation (especially at the injection site), and bone pain.³¹ However, as with bisphosphonates, denosumab can cause osteonecrosis of the jaw in patients with metastases from prostate cancer and other solid tumors; thus, preventive dentistry before initiating therapy is recommended.³²

TAKE-HOME MESSAGE 

Osteoporosis in men is underdiagnosed, underreported, and undertreated, leading to worse outcomes in these patients. Men at risk of osteoporosis or suspected to have osteoporosis should receive a DXA scan, which easily identifies the condition as well as osteopenia, a precursor to osteoporosis. For hypogonadal men without prostate cancer, testosterone replacement therapy is appropriate. Treatment of men with prostate cancer consists of vitamin D and calcium supplementation with concomitant use of bisphosphonates or denosumab. In addition, all men should be encouraged to engage in lifestyle interventions that reduce bone damage, such as limiting alcohol consumption, engaging in regular physical activity, and abstaining from smoking. Prompt diagnosis and intervention are essential in reducing morbidity and mortality, while significantly improving men’s quality of life.  ■

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