Continuing Education Activity

Osteoporosis is a silent disease characterized by low bone mass and structural deterioration of bone microarchitecture leading to fragility and increased risk of fractures. Classically, it has been more studied in postmenopausal women due to the known effects of estrogen deficiency during that period in females and associated increased prevalence of osteoporosis. More recently, however, the medical society has increasingly acknowledged the significant impact the burden of osteoporosis has caused in males. Unfortunately, the shortage of studies in men and lack of consensus among medical societies challenge the treatment of osteoporosis in men. This activity reviews the evaluation and treatment of osteoporosis in males with the currently available literature and highlights the role of multidisciplinary care in the management of osteoporosis in males.

Objectives:

• Identify the etiology and risk factors associated with osteoporosis in males.
• Review the presentation of osteoporosis in males.
• Outline the current options available and possible future treatment for osteoporosis in males.
• Describe some interprofessional team strategies for improving care and outcomes in males with osteoporosis.

Introduction

Osteoporosis is a silent disorder characterized by reduced bone density and structural deterioration of bone microarchitecture leading to fragility and increased risk of fractures. It has been mainly considered a post-menopausal condition, due to the known effects of reduced estrogen on the decrease in bone mass in females. However, the acknowledgment of the osteoporosis burden in the male population has grown in the past decades, associated with the increase of fragility fractures in the population, likely due to longer life span observed worldwide, a more sedentary lifestyle, and increased prevalence of risk factors.[1]

The World Health Organization (WHO) and the International Society for Clinical Densitometry (ISCD) have defined diagnostic criteria for low bone mass (osteopenia) and osteoporosis based on bone mineral density (BMD) measurements in a dual-energy x-ray absorptiometry (DEXA) scan compared with a reference population. For males, it is recommended to use the same thresholds as females although the densitometric definition is not as well standardized as in postmenopausal women.[2]  

Although the prevalence of osteoporosis is higher in females, males present with higher mortality risk following a fracture. That is true for both vertebral and non-vertebral fractures.[3][4] Despite high mortality and morbidity in males, unfortunately, most randomized controlled trials for osteoporosis treatment only include postmenopausal females, resulting in a challenge in managing osteoporosis in males.

Etiology

Despite hormonal and biomechanical advantages compared to females, approximately one-third of men still may experience one or more osteoporotic fractures in their life. Osteoporosis in men can be classified into two categories, primary and secondary. Secondary causes represent about 50% of cases in males.[5] However, primary etiology can be underestimated due to less active diagnosis search in patients without risk factors.

Primary osteoporosis can be further divided into (1) involutional osteoporosis, i.e patients older than 70 years old when no other risk factor is present, and (2) idiopathic osteoporosis, i.e patients younger than 70 years old with no apparent risk factor.[3]

Idiopathic osteoporosis occurs in men younger than 70 years old. In these individuals, osteoporosis is considered idiopathic since there is no obvious reason for premature low bone mass, however that could be multifactorial, related to inadequate peak in bone mass, undiagnosed genetic problems, sedentary lifestyle, or other undiagnosed comorbidities. These patients also might have a mild defect in aromatization.[6]

The major causes of secondary osteoporosis are hypogonadism (including men on androgen deprivation therapy for prostate cancer), alcohol abuse, glucocorticoid excess (endogenous or exogenous), malabsorption (including inflammatory bowel disease, primary biliary cirrhosis and post gastric bypass), chronic kidney disease (associated secondary hyperparathyroidism), primary hyperparathyroidism, hyperthyroidism, systemic illnesses (malignancy, multiple myeloma, mastocytosis), chronic obstructive pulmonary disease, HIV infection, inflammatory rheumatic diseases, anticonvulsants, and chemotherapeutics. More recently type 1 and type 2 diabetes have also been recognized as a risk factor for osteoporosis, despite patients usually presenting with normal or above normal BMD on the DEXA scan.[3]

The mechanisms behind increased bone fragility in diabetes mellitus are multifactorial and include microvascular disease, oxidative stress, advanced glycation endproducts that compromise the quality of collagen type I, and increased inflammatory factors and adipokines. Additional factors include certain diabetes medications such as thiazolidinediones and canagliflozin and an increased propensity for falls, likely due to hypoglycemia.[7][8]

Other than the conditions mentioned above that are causes of secondary osteoporosis in male, non-modifiable risk factors are age equal or more than 70 years old, white ethnicity, and delayed puberty. Modifiable risk factors are alcohol abuse, smoking, low BMI, and a sedentary lifestyle.

Epidemiology

In 2010 it was estimated that 8.2 million women and 2.0 million men in the United States had osteoporosis, while approximately 27.3 million women and 16.1 million men had osteopenia.[9] Although the prevalence of osteoporosis in women is higher than in men, about 30-40% of osteoporotic fractures occur in men.[10] 

As stated before, males present with higher mortality risk following a fracture in any site. An observational study in Australia revealed that mortality ratios in women were 2.18 (95% CI 2.03–2.32) for proximal femur, 1.66 (1.51–1.80) for vertebral, and 1.92 (1.70–2.14) for other major fractures, compared to 3.17 (2.90–3.44) for proximal femur, 2.38 (2.17–2.59) for vertebral, and 2.22 (1.91–2.52) for other major fractures in males.[4]

Fracture incidence in men has classically a bimodal peak at 15-45 years and after 70 years. The first peak is likely secondary to traumatic fractures while the second peak is related to osteoporosis or osteopenia.  Men have hip fractures on average 10 years later than women. This fact is especially important in aging populations since both males and females are experiencing longer life expectancy. A 50-year old man has a lifetime risk of osteoporotic fractures of 13-25%, but this frequency depends on other factors, including race, ethnicity, and geography.[11] There is a higher prevalence in Northern Europe and North America males, compared to blacks, Asians, and Hispanics.[10][12]

Pathophysiology

Bone mineral density (BMD) is expressed by the mass of calcium hydroxyapatite present in a given area or volume of bone in a unit of mass/area (g/cm2) or mass/volume (g/cm3), respectively.[13] The most important determinants for the bone density of an individual are the peak of bone mass and the rate of bone loss.

The peak bone mass (PBM) is the total amount of bone tissue at the end of skeletal maturation. In newborns, there is no evidence of a gender-related difference in bone mass.[14] The similarity in bone mass in both genders is consistent until the beginning of puberty.[15] The increase in bone mass starts on average 2 years earlier in females compared to males.[16] During puberty, periosteal bone formation is greater in males resulting in increased cortical width, whereas females have less periosteal bone formation but more endocortical apposition. The increased androgens in males, as well as growth hormone (GH), and insulin-like growth factor 1 (IGF-1) additively stimulate the apposition of periosteal bone in men, whereas estrogens inhibit periosteal apposition in females, culminating in wider bones in men compared to women.[1] 

In general, peak bone mass is 8-10% higher in men compared to women, which can also justify a decreased prevalence of osteoporosis in men.[1] 

Elderly men have a progressive and slow decrease in sex hormones as opposed to the sudden decrease observed in women after menopause. Aging is accompanied by an increase in sex hormone-binding globulin (SHBG) serum levels, resulting in a reduced availability of free testosterone and estradiol. Estradiol is important in males for the maintenance of BMD and bone remodeling, whereas free testosterone promotes periosteal apposition.  Men with inactivating mutation on the estrogen receptor gene or with aromatase deficiency lack epiphyseal fusion and have higher bone remodeling markers and low bone mass, despite higher testosterone plasmatic levels. These patients usually respond to estrogen with an increase in bone mass, endorsing the importance of estrogen in the regulation of male bone metabolism.[17][18]

Androgens also play a role in the preservation of muscle mass, and with the progressive androgen deficiency seen with aging, men develop sarcopenia, with decreased body strength and increased risk of falls.[19] A European study from 2013 revealed that older men with sarcopenia were more likely to have densitometric osteoporosis compared to men with normal relative appendicular skeletal muscle mass.[20]

In age-related osteoporosis, insulin-like growth factor-1 (IGF-1) decline is also observed which might be associated with an increase in SHBG, as IGF-1 inhibits SHBG production by hepatocytes. The decrease in IGF-1 also impairs the production of GH resulting in reduced periosteal apposition, bone remodeling, and muscle mass.

There are differences in the way men and women lose bone mass upon aging. Bone loss usually starts in the 4th decade for both, however, while bone loss accelerates in women after menopause, it is more gradual in men. In secondary causes of osteoporosis, such as when undergoing androgen deprivation therapy (ADT) or chronic glucocorticoid therapy, men can experience a sharper decrease in bone mass with a further higher risk of fracture. During the normal aging process, trabecular bone loss in women involves the decline in the number of trabeculae, whereas in men the trabeculae become thinner, but the quantity remains relatively constant. This difference in the mechanism of bone loss could also contribute to the decreased fracture risk in men.[21][5]

History and Physical

While investigating men with osteoporosis it is important to inquire about calcium and vitamin D intake, sun exposure, prior fractures and associated mechanism of trauma, and history of height loss.

The physical examination in a patient with primary osteoporosis is usually unremarkable unless if advanced disease when patients can present with kyphosis, and reduced height from prior measured height if previous compression vertebral fractures. A general physical exam should also include evaluation of gait, balance, mobility, overall frailty, and muscle mass.

To aid in finding a secondary and/or reversible cause of osteoporosis, specific information and physical exam findings should be elicited in a systematic way to rule out the following conditions:

• Use of medications such as anticonvulsants, chemotherapeutics, glucocorticoids, cyclosporin, tacrolimus, aromatase inhibitors, GnRH agonists, levothyroxine suppressive therapy (e.g post thyroid cancer), HIV medications, and long term heparin. Long term opioid use can also indirectly cause osteoporosis by provoking hypogonadism.
• Endocrine causes: hyperthyroidism, exogenous or endogenous hypercortisolism, hyperparathyroidism, hypogonadism, type 1 or type 2 diabetes, vitamin D deficiency or resistance, delayed puberty, androgen insensitivity, and growth hormone deficiency.
• Malabsorption: celiac disease, post-bariatric surgery, inflammatory bowel disease. 
• Hematologic causes: multiple myeloma, systemic mastocytosis, chronic hemolytic anemia.
• Connective tissue diseases: osteogenesis imperfecta, Marfan Syndrome, Ehlers-Danlos syndrome, and hereditary hypophosphatemic rickets. 
• Miscellaneous: chronic liver disease, chronic kidney disease, hypercalciuria, anorexia nervosa, chronic obstructive pulmonary disease, rheumatoid arthritis, malignancy, and organ transplantation.

Lastly, it is mandatory to obtain a full social history inquiring about smoking, alcohol abuse, and a sedentary lifestyle.  [22][23]

Evaluation

Recommendations for DEXA Scan

In 2012 the Endocrine Society published the guideline for Osteoporosis in men which is still updated in regards to the indications for DEXA scan and investigation for osteoporosis in males. It recommends testing men 70 years or older and aged 50 to 69 years if risk factors are present. DEXA scan of the spine and hip is recommended in men at risk for osteoporosis and the forearm DEXA scan (proximal 1/3 portion of dominant radius) is recommended when the lumbar spine or hip BMD cannot be reliably interpreted and for men with hyperparathyroidism or on androgen deprivation therapy.[22] The ISCD and NOF have the same recommendations.[24] The United States Preventative Services Task Force did not recommend an established screening for men due to the consideration of insufficient evidence.

Interpretation of DEXA Scan

For patients ≥ 50 years old, a T-score less than or equal to -2.5 SD (compared to a young adult female) is used for the diagnosis of osteoporosis according to the WHO and the ISCD. However, there is controversy since randomized trials of osteoporosis therapy in men used T-scores calculated using male normal controls. A T-score between -1.0 and -2.5 suggests the diagnosis of osteopenia in males in this age group.[22]

For patients younger than 50 years old, the ISCD recommends using a Z-score less than or equal to -2.5 D for the diagnosis of osteoporosis(which would compare males with peers of the same age if these data are available or with women on the same age if male data are not available). A Z-score between -1.0 and -2.5 suggests a diagnosis of osteopenia in males in this age group. A history of fragility fracture or risk factors for osteoporosis should also be considered for the diagnosis and decision to treat. In a patient with a fragility fracture, a densitometric diagnosis of osteoporosis is not needed to initiate treatment.

In patients younger the 50 years old, the diagnosis of osteoporosis should not be made based on BMD alone.

For patients with densitometric osteopenia without prior history of osteoporotic fractures, it is recommended to use the FRAX calculator to determine the decision for treatment.  In patients 50 years and older with densitometric osteopenia and a 10-year hip fracture probability 3% or higher or a 10-year major fracture probability 20 % or higher based on the U.S.-adapted WHO absolute fracture risk model warrants treatment.[23]

Other Imaging 

In patients with osteopenia or osteoporosis who might have had undiagnosed vertebral fractures, thoracic and lumbar spine imaging should be obtained by Vertebral Fracture Assessment (VFA). It has lower cost and radiation exposure than regular plain radiographs and can be obtained at the same time as the DEXA scan. If VFA is not available then lateral spine radiographs should be obtained. [22]

Lateral spine radiography should also be considered:

• In men aged 80 and older if BMD T-score is ≤−1.0 at the spine, total hip, or femoral neck 
• In men aged 70 to 79 if BMD T-score is ≤−1.5 at the spine, total hip, or femoral neck
• In 50 years or older men with specific risk factors: Low-trauma fracture during adulthood (age 50 and older); historical height loss of 1.5 inches (4 cm) or more when compared to peak height at age 20; prospective height loss of 0.8 inches or more (2 cm) with previously documented height; recent or current long-term glucocorticoid treatment.
• If DEXA scan is not available, vertebral imaging may be considered based on age and risk factors.[24] 

Laboratory Evaluation

Initial laboratory evaluation for males with osteoporosis should include serum calcium, phosphate, creatinine with estimated glomerular filtration rate, alkaline phosphatase, liver function, 25(OH)vitamin D, total testosterone, complete blood count, and 24-h urinary calcium (including creatinine and sodium). If a specific cause of osteoporosis is suggested by history and physical exam, a more thorough investigation can be pursued, including free testosterone, prolactin, IGF-1, serum protein electrophoresis with free and light chains and/or urine protein electrophoresis, tissue transglutaminase antibodies, thyroid function tests, and PTH levels. In order to rule out endogenous hypercortisolism, 1 mg-dexamethasone suppression test is the preferred initial investigation, but two different essays are ideal to confirm endogenous hypercortisolism. The second test can be either free urinary cortisol (urine 24h) or nocturnal salivary cortisol. 

Note that the list for secondary causes of osteoporosis is extensive and the laboratory investigation needs to follow clinical suspicion.[24]  

Biochemical markers of bone turnover can also be checked at baseline to aid in risk assessment and to serve as an additional monitoring tool when treatment is initiated, also to assess compliance with treatment. However, their role in patient individual care is not well established.

Treatment / Management

Indications for Treatment

1) T-score less than or equal to -2.5 SD on the femur or lumbar spine in patients older than 70 years old

2) T-score between -1 and -2.5 with a 10-year probability of more than 3 percent hip fracture or more than 20 percent probability of osteoporosis-related major fracture on FRAX country-specific. 

3) Patients with osteoporotic fractures

Management

1) Lifestyle changes: Recommendations based on studies aimed at preserving bone mass in men are similar to those recommended for women. They include a balanced diet with adequate protein and dairy intake, regular physical activity, and avoiding excessive alcohol consumption and smoking[25][26]. At least 30-40 mins of weight-bearing exercise 3-4 times per week should be encouraged. 

2) Fall precautions: The NOF recommends assessing patients with risk factors for falls and offering appropriate modifications (e.g., home safety assessment, physical therapy, correction of vitamin D insufficiency or deficiency, caution with central nervous system depressant medications, avoidance of hypotension, and visual correction).

3) Calcium and Vitamin D supplementation: There is evidence that calcium and vitamin D given together reduce fractures in multiple studies, including a pooled analysis of 68500 patients with a male population of 14.7% from seven trials in the US and Europe.[27] Vitamin D given alone (400-800 IU) showed no effect in reducing fractures. In this study, calcium and vitamin D together reduced hip and total fractures, independent of age, sex, or previous fractures. However, there is also some controversial evidence that calcium supplementation can increase cardiovascular disease (CVD) frequency, in females[28] and males. The NIH-AARP Diet and Health Study assessed calcium intakes at baseline in 388,229 men and women aged 50–71 years. Patients were followed for 12 years and cardiovascular events were identified. Authors found that men on calcium supplementation had a 20% higher risk of CVD death, which was not true for women.[29]

Therefore, the NOF currently recommends a diet with adequate amounts of total calcium (at least 1000 mg/day for men 50–70 and 1200 mg/day for men 71 and older) and to add calcium supplements only if dietary intake is insufficient. It also advises on vitamin D intake (800–1000 IU/day), including supplements if necessary for individuals age 50 and older to achieve a vitamin D level of 30 ng/ml or greater.[24] For people with vitamin D insufficiency (level <30 ng/ml but >20ng/ml), these optimal vitamin D levels can be achieved with 1000–2000 IU of vitamin D daily. For vitamin D deficient patients (level <20 ng/ml), 50,000 U weekly of cholecalciferol should be prescribed for 8 weeks or 300,000 every 3 months may be required, followed by maintenance therapy with the regimen mentioned for vitamin D insufficiency. 

4) FDA-approved anti-reabsorptive drugs available for the treatment of primary osteoporosis in males:

a) Bisphosphonates are synthetic analogs of inorganic pyrophosphate which are deposited in the bone matrix. They act in bone resorption sites and are the first-line treatment of osteoporosis. Alendronate, risedronate, and zoledronic acid are approved for the treatment of primary osteoporosis in post-menopausal women, men, and glucocorticoid-related osteoporosis. They have shown to reduce vertebral and non-vertebral fractures.  In a study with more than 2100 subjects (25% men) who had undergone surgery for a hip fracture, annual treatment with zoledronic acid reduced the risk of recurrent fractures when initiated within 90 days of the event, after a median follow up of 1.9 years. [30][31][32][33] 

Drug administration:  Alendronate and risedronate tablets must be taken on an empty stomach, with 8 oz of plain water. Patients must wait at least 30 min after taking these medications before eating, drinking, or taking any other medication. During that time they should remain upright, either sitting or standing. Zoledronic acid is given IV, over at least 15 min, once a year or every 2 years. Patients may experience flu-like symptoms after administration, which can be prevented with adequate hydration and pretreatment with acetaminophen.

Drug safety: Side effects are class-related and include gastrointestinal problems, such as gastritis and esophagitis. All bisphosphonates are contraindicated in patients with an estimated GFR below 30–35 ml/min. Osteonecrosis of the jaw (ONJ) is a rare side effect, more associated with high-dose IV bisphosphonate use in patients with cancer. The risk increases with duration >5 years.[34] Also rare, low-trauma atypical femur fractures may also be associated with long-term use of bisphosphonates, also more than 5 years. Patients can have prodromes such as the bilateral or unilateral thigh or groin pain.[35]

b) Denosumab: it is a RANK-L monoclonal antibody. By binding the RANK-L with high affinity, it prevents the ligand from activating its receptor, the receptor activator of nuclear factor-kappa B (RANK), on the surfaces of osteoclasts, inhibiting bone reabsorption.  It was approved by use in men with osteoporosis after the study ADAMO which revealed an increase in BMD of the lumbar spine, femur, and distal radius[36]. 

Another significant multicenter study that included patients undergoing treatment for non-metastatic prostate cancer on anti-androgenic drugs resulted in a significant increase in BMD of the lumbar spine (8.0%), femoral neck (4.9%) and distal third of the radius (6.9%) during the 3-year follow up. Moreover, it also showed a 45% reduction in the risk of any new fractures and a decrease in the incidence of new vertebral fractures. 

It is FDA approved for the treatment of osteoporosis in postmenopausal women, in men at high risk of fracture with primary osteoporosis, to treat bone loss in women with breast cancer on an aromatase inhibitor, and male with prostate cancer on androgen deprivation therapy who are at high risk of fracture.[3][22]

Drug administration: It has to be administered by a health professional, 60 mg every 6 months subcutaneously.

Drug safety: It may cause hypocalcemia, which has to be corrected before starting denosumab. It can increase the risk of serious skin infections (cellulitis) and skin rash. As bisphosphonates, it has also been rarely associated with the development of ONJ, although much more common when used in patients with cancer at higher doses. It has also been rarely associated with the development of atypical femur fractures. If chosen to be discontinued, another agent should be promptly initiated since a rapid bone loss has shown to happen upon discontinuation.  

5) FDA-approved anabolic drugs available for the treatment of primary osteoporosis in males:

a) Teriparatide (recombinant human PTH 1-34) is a synthetic polypeptide with a similar sequence of the amino acids 1-34 of the amino-terminal region of the endogenous human PTH (PTH 1-84), which is the biological action sequence. It binds with similar affinity to the G protein-coupled receptor because it is identical to the biologically active fraction of PTH 1-84.

It is approved by the FDA for the treatment of osteoporosis in postmenopausal women and men at high risk for fracture. It is also approved for treatment in men and women and glucocorticoid-related osteoporosis if high risk for fracture.[37] There is strong evidence of the efficacy of teriparatide in increasing BMD and reducing vertebral and non-vertebral fractures in postmenopausal women.[38] A follow-up observational study in male patients who participated in an RCT with teriparatide showed those patients had fewer vertebral fractures [39], however, the evidence regarding non-vertebral fractures is not consistent. 

Drug administration: it is administered by 20 μg daily subcutaneous injection and treatment should not exceed 18 to 24 months. When treatment is discontinued bone loss can be rapid and either bisphosphonates or denosumab should be considered to maintain BMD. 

Drug safety: possible side effects are leg cramps, nausea, and dizziness. It has shown a dose-dependent increase in the incidence of osteosarcoma in rats (on much higher doses per kg than used for humans.) Therefore, patients with an increased risk of osteosarcomas, such as patients with Paget’s disease of bone (PDB), history of prior radiation therapy of the skeleton, bone metastases, history of primary bone malignant tumor, or hypercalcemia should not receive teriparatide if require treatment for osteoporosis. Patients with PDB and osteoporosis would benefit from zoledronic acid for both conditions.  

6) Hormonal therapy: Testosterone is the main therapy in hypogonadal patients increasing bone mineral density and decreasing sarcopenia. For patients with hypogonadism with high risk for fracture or with contraindications for testosterone replacement, it is recommended to add nonhormonal pharmacologic therapy. The indications for adding nonhormonal therapy are: patients on high-dose glucocorticoids, frequent falls, history of a recent fragility fracture, particularly with a BMD T-score below -2.5 at any skeletal site, T-scores below -3.5 or even below -3.0 if they have other risk factors for fracture, T-score <-2.5 (or fragility fracture) even after receiving adequate testosterone therapy for two years. [40]

7) Possible future drugs for osteoporosis in males: 

a) Abaloparatide (PTHrP 1-34) is a synthetic analog of PTH related peptide (PTHrP) with 76 percent homology that binds more selectively than teriparatide to the PTH type 1 receptor (PTH1R). It binds selectively to the RG conformation of that receptor what confers a more transient response, favoring bone formation avoiding more prolonged activation and its undesired effects (eg, bone resorption, hypercalcemia). It has been available in the United States since 2017 and has proven to be efficacious in postmenopausal women with osteoporosis, reducing the risk of new vertebral and nonvertebral fractures over 18 months. Further research is needed to understand the risks and benefits and its efficacy versus other therapies. A phase 3 trial is ongoing to evaluate its effect on osteoporosis in males.[41]

c) Romosozumab: a humanized monoclonal antibody that binds and inhibits sclerostin. Sclerostin is secreted by osteocytes and regulates bone formation. Its inhibition by romosozumab has shown a dual effect of bone formation and decreased bone resorption. A phase III trial (FRAME) has shown a significant increase in BMD at the lumbar spine, hip, and a significant reduction of vertebral and nonvertebral fractures following 12 months of therapy in postmenopausal women. In 2018, a phase III trial with 245 male subjects also showed increased spine and hip BMD following 12 months of treatment with romosozumab, but there were safety concerns due to a low but significant increase in cardiovascular events in the medication group. [42][43] Another study comparing romosozumab and alendronate in postmenopausal women also had more cardiovascular events on the romosozumab group, although a low number of cases (0.8 versus 0.3 percent).[44] Currently, it has FDA approval only for postmenopausal women with no significant cardiovascular risk. It has not been approved for males yet.

Sequential Therapy 

When diagnosed in younger individuals, it is preferred to manage patients with sequential monotherapy, as patients will more likely need to be on long-term therapy. As the majority of the anti-osteoporotic medications can not be continued indefinitely, this management is preferred to keep patients covered for the longest period, while not increasing the risk of major side effects. 

For more severe osteoporosis, one option is to follow an anabolic therapy with an antiresorptive agent. To prevent the loss of the newly formed bone, an antiresorptive agent must begin within 1 month of completing the course of anabolic therapy. It is not recommended to combine teriparatide and bisphosphonate. An RCT showed that patients on teriparatide monotherapy had a higher increase in BMD compared with those on a combination of alendronate and teriparatide. Alendronate has shown to attenuate the stimulus for bone formation promoted by teriparatide when given in combination.[45]

Duration of Treatment

No anti-osteoporotic therapy should be considered indefinite. Except for bisphosphonates, all other medications produce effects that wane relatively quickly after discontinuation. In contrast, bisphosphonates retain residual effects following treatment discontinuation. Therefore, it is recommended to discontinue bisphosphonates usually after 5 years of continuous use of the oral presentations (alendronate and risedronate) and after 3 years for zoledronic acid, to reduce the risk of major side effects, such as ONJ and atypical femur fractures which become more common after 5 years of continuous use.[46][47] For patients who continue to have a high risk for fracture, treatment with a bisphosphonate should be resumed after a pause of 1-2 years or alternative therapy should be considered. 

Differential Diagnosis

Possible differential diagnoses that need to be considered in a patient presenting with a spontaneous fracture or after low impact trauma are: 

1) Vitamin D deficiency (less than 20nmol/L) or insufficiency (less than 30 nmol/L) which can cause osteomalacia and increased risk of hip fractures in men and women. This is reversible after treatment with cholecalciferol. 

2) Solid tumors with bone metastasis are common causes of fractures. Solid tumors more associated with bone metastasis are lung, breast, and prostate. 

3) Hematologic malignancies can commonly present with bone fracture, multiple myeloma is the most common primary malignant bone tumor, although it is considered a bone marrow tumor.

4) Primary bone tumors are much less common than bone metastasis, however, should also be considered as potential causes of fractures. The most common malignant primary bone tumor is osteosarcoma, although occurs more frequently in younger patients (2nd or 3rd decade).

5) Avascular necrosis of the femur should also be ruled out when a patient presents with subtle pain and limited range of motion of the hip, especially when not associated with trauma and in the presence of risk factors (glucocorticoid use, sickle cell disease).

Pertinent Studies and Ongoing Trials

A phase 3 trial is currently happening to evaluate the efficacy and safety of subcutaneous abaloparatide 80 mcg per day in men with osteoporosis compared to placebo by change in bone mineral density after 12 months. 

Prognosis

As stated before, although the prevalence of osteoporosis is higher in females than in males, the morbidity and mortality after osteoporotic fractures are worse in men than in women.[48]  A large Canadian survey showed that approximately 10% of elderly males died during hospitalization following a hip fracture and 37.5% of those who were discharged died within the year. Furthermore, men become more dependent than women after a hip fracture has occurred.[49]

Complications

Complications associated with fractures in males can be related to prolonged immobilization, such as venous thromboembolism or, if a major fracture, there is the rare risk of air embolism. 

Patients experiencing vertebral compression fractures also have an increased risk of cord compression if the affected vertebra is not stabilized. 

Consultations

Rheumatology or Endocrinology should be consulted for patients with severe osteoporosis to aid in management. 

Patients should be evaluated by Endocrinology to rule out endocrine causes of secondary osteoporosis if warranted per history and physical signs. 

Orthopedics should be consulted if acute fracture or history of compression fractures to consider vertebroplasty or kyphoplasty. They also should be consulted if non-vertebral fractures happen. 

Deterrence and Patient Education

It is important to educate and assess patients for the prevention of fractures, by reducing the risk of falls, such as wearing appropriate shoes, removing home hazards, lighting up the living space, using assistive devices.

It is also important to inform patients about the importance of obtaining calcium from the diet and supplement with calcium tablets only if the required amount can not be obtained from the diet. 

Pearls and Other Issues

• Osteoporosis in men is a growing problem worldwide and in the USA. The incidence of osteoporosis in males is growing due to multiple factors, including aging of the population, more sedentary lifestyle. It is usually overlooked due to culturally be considered a postmenopausal female medical problem. However, men experience higher mortality and morbidity following fractures. 
• About 50% of men tend to have an identifiable and potentially secondary cause of osteoporosis. Therefore it is mandatory to perform a careful evaluation for all the possible causes and provide adequate treatment if available.
• Treatment involves lifestyle changes, supplementation of calcium and vitamin D, treatment of secondary causes, and anti-osteoporosis therapy.
• New drugs have been developed and new studies have been including males more frequently.
• Anti-osteoporotic drugs that have shown efficacy in males are bisphosphonates (only alendronate, risedronate, and zoledronic acid), denosumab, and teriparatide. 

Enhancing Healthcare Team Outcomes

The diagnosis and management of osteoporosis are best achieved with an interprofessional team that consists of a rheumatologist and/or endocrinologist, primary care provider, nurse practitioner, dietitian, and radiologist. Patients at risk should be screened as appropriate to identify those who warrant further investigation and/or treatment to prevent fractures and consequent morbidity and mortality. The primary care provider and nurse practitioner ideally should educate the patients on lifestyle interventions that include discontinuing tobacco, excessive alcohol, promoting a healthy lifestyle, including calcium and vitamin D supplementation if adequate, lean protein ingestion, and participation in physical activity. For males treated with bisphosphonates, regular monitoring is mandatory as these drugs have potential adverse effects, also to ensure adequate response and compliance.[50][51] 

Level 3 Evidence.