madman
Super Moderator
Male osteoporosis (2022)
Leonardo Bandeira, Barbara C. Silva, John P. Bilezikian
ABSTRACT
Osteoporosis, a disease classically attributed to postmenopausal women, is underappreciated, underdiagnosed, and undertreated in men. However, it is not uncommon for osteoporotic fractures to occur in men. About 40% of fractures occur in men with an incidence that has increased over the years. After a first fracture, the risk of a subsequent episode, as well as the risk of death, is higher in the male than in the female population. Despite these facts, only 10% of men with osteoporosis receive adequate treatment. Up to half of the cases of male osteoporosis have a secondary cause, the most common being hypogonadism, excessive alcohol consumption, and chronic use of glucocorticoids. The International Society for Clinical Densitometry (ISCD) recommends using the female database for the diagnosis of osteoporosis by DXA (T-score ≤ -2.5 in men over 50 years old). In addition, osteoporosis can also be diagnosed independently of the BMD if a fragility fracture is present, or if there is a high risk of fractures by FRAX. Treatment is similar to postmenopausal osteoporosis because the data regarding changes in bone density track closely to those in women. Data concerning fracture risk reduction are not as certain because the clinical trials have included fewer subjects for a shorter period of time. In men with symptomatic hypogonadism, testosterone replacement, if indicated, can improve BMD.
INTRODUCTION
Osteoporosis is a disease characterized by reduced bone mass and deterioration of skeletal microarchitecture, resulting in increased bone fragility and risk of fractures. It is the most common metabolic bone disease and its main outcome, osteoporotic fractures, significantly increase morbidity and mortality. Traditionally a disease of women, osteoporosis is underappreciated, underdiagnosed, and undertreated in men. Although more common in women, the disease occurs with considerable frequency in the male population, with a prevalence of about 12% worldwide and reaching more than 20% in some regions of the world (1-3). Furthermore, the morbidity and mortality due to fractures are significantly higher in men than in women, perhaps because they occur 5 to 10 years later in men, and thus, are accompanied by more comorbidities (4,5). This narrative review provides an update on several aspects of male osteoporosis.
*EPIDEMIOLOGY
*PATHOPHYSIOLOGY
*ETIOLOGY
*DIAGNOSIS
TREATMENT
Non-pharmacological
Nonpharmacological measures such as physical activity, limited alcohol intake, and smoking cessation should be recommended for all. In addition, vitamin D supplementation to maintain serum levels of 25-OHvitamin D greater than 30 ng/mL, and a daily intake of 1000 to 1200 mg of calcium through diet or supplements are important nonpharmacological measures (42-47). If any secondary cause of osteoporosis is identified, it should be treated (36).
Bisphosphonates
By inhibiting osteoclasts, bisphosphonates reduce bone resorption. Alendronate, risedronate, and zoledronic acid are the main representatives of this class, all of which are approved by the regulatory agencies for the treatment of osteoporosis in men. The effects of bisphosphonates on BMD and bone turnover appear to be similar between men and women (48).
Denosumab
By binding to nuclear factor-kappa beta activating receptor-ligand (RANKL), denosumab prevents the interaction between RANKL, a powerful bone-resorbing cytokine, to its receptor RANK on osteoclasts. This results in a powerful inhibition of these cells and thus an antiresorptive effect (55).
Teriparatide
Teriparatide (PTH 1-34) comprises the initial 34 aminoacids of the 84-aminoacid PTH molecule. Insight into the therapeutic potential of PTH came from the observation that PTH, when administered intermittently and in low doses, stimulates bone formation. Thus, it is an osteoanabolic agent (60-62).
Abaloparatide
Abaloparatide is an analog of PTHrP, designed to maximize its interaction with the configuration of the PTH/PTHrP receptor that favors anabolic activity (67).
Safety of teriparatide and abaloparatide
The US Food and Drug Administration (FDA) has removed the boxed warning for both teriparatide and abaloparatide with regard to osteosarcoma and to the duration of use. This recommendation is based upon abundant surveillance data for teriparatide that did not show any oncogenic signals in human subjects after over a decade of careful monitoring (69,70).
Testosterone
Hypogonadism is a major etiology of osteoporosis in men. Testosterone deficiency is known to reduce BMD and increase the risk of fractures in men (18,22,25), which would justify its use in hypogonadal patients with osteoporosis. Testosterone replacement increases BMD, reduces bone turnover markers, and improves bone strength in men with hypogonadism (71-73). On the other hand, its use in the elderly with normal serum testosterone levels did not change BMD (74). Data regarding the effectiveness of testosterone treatment in fracture reduction are limited (75).
The Endocrine Society guidelines for male osteoporosis recommend testosterone replacement in hypogonadal patients (testosterone levels below 200 ng/mL in at least 2 measurements) who are symptomatic or who have known causes of hypogonadism (e.g. pituitary or testicular disorder) if there are no contraindications. However, testosterone is not the first-line therapy for hypogonadal men who are at high risk of fractures. Rather, an approved medication for osteoporosis is recommended and should be associated with testosterone therapy if there is a formal indication for testosterone replacement. Also, if there is a contraindication to an approved agent for osteoporosis in patients at high risk of fractures and testosterone levels below 200 ng/dL, testosterone therapy may be an alternative even with no standard indication for testosterone replacement (36).
Romosozumab
Romosozumab, an antisclerostin antibody, was developed to block the effects of sclerostin, a regulator of the Wnt bone formation signaling pathway. By blocking sclerostin, romosozumab was designed to be an osteoanabolic agent. Indeed, it is. However, another effect of romosozumab is as an antiresorptive agent. This mechanism of action is unique in that it is a dual-action drug, namely increasing bone formation and inhibiting bone resorption.
*Selection of initial therapy
*Monitoring therapy
In conclusion, this review summarizes the most recent data on the epidemiology, pathophysiology, etiology, diagnosis, and treatment of male osteoporosis. Despite a frequent condition, male osteoporosis is still underappreciated by physicians, with less than 20% of men being treated, even considering those with previous fractures. With the increase in life expectancy, osteoporosis has become more prevalent in men and its main outcome, namely fracture, underscores a major health burden in this population, in addition to remarkable costs for health systems around the world. Thus, it is urgent to increase awareness of male osteoporosis, reducing undertreatment and improving care for this population.
Leonardo Bandeira, Barbara C. Silva, John P. Bilezikian
ABSTRACT
Osteoporosis, a disease classically attributed to postmenopausal women, is underappreciated, underdiagnosed, and undertreated in men. However, it is not uncommon for osteoporotic fractures to occur in men. About 40% of fractures occur in men with an incidence that has increased over the years. After a first fracture, the risk of a subsequent episode, as well as the risk of death, is higher in the male than in the female population. Despite these facts, only 10% of men with osteoporosis receive adequate treatment. Up to half of the cases of male osteoporosis have a secondary cause, the most common being hypogonadism, excessive alcohol consumption, and chronic use of glucocorticoids. The International Society for Clinical Densitometry (ISCD) recommends using the female database for the diagnosis of osteoporosis by DXA (T-score ≤ -2.5 in men over 50 years old). In addition, osteoporosis can also be diagnosed independently of the BMD if a fragility fracture is present, or if there is a high risk of fractures by FRAX. Treatment is similar to postmenopausal osteoporosis because the data regarding changes in bone density track closely to those in women. Data concerning fracture risk reduction are not as certain because the clinical trials have included fewer subjects for a shorter period of time. In men with symptomatic hypogonadism, testosterone replacement, if indicated, can improve BMD.
INTRODUCTION
Osteoporosis is a disease characterized by reduced bone mass and deterioration of skeletal microarchitecture, resulting in increased bone fragility and risk of fractures. It is the most common metabolic bone disease and its main outcome, osteoporotic fractures, significantly increase morbidity and mortality. Traditionally a disease of women, osteoporosis is underappreciated, underdiagnosed, and undertreated in men. Although more common in women, the disease occurs with considerable frequency in the male population, with a prevalence of about 12% worldwide and reaching more than 20% in some regions of the world (1-3). Furthermore, the morbidity and mortality due to fractures are significantly higher in men than in women, perhaps because they occur 5 to 10 years later in men, and thus, are accompanied by more comorbidities (4,5). This narrative review provides an update on several aspects of male osteoporosis.
*EPIDEMIOLOGY
*PATHOPHYSIOLOGY
*ETIOLOGY
*DIAGNOSIS
TREATMENT
Non-pharmacological
Nonpharmacological measures such as physical activity, limited alcohol intake, and smoking cessation should be recommended for all. In addition, vitamin D supplementation to maintain serum levels of 25-OHvitamin D greater than 30 ng/mL, and a daily intake of 1000 to 1200 mg of calcium through diet or supplements are important nonpharmacological measures (42-47). If any secondary cause of osteoporosis is identified, it should be treated (36).
Bisphosphonates
By inhibiting osteoclasts, bisphosphonates reduce bone resorption. Alendronate, risedronate, and zoledronic acid are the main representatives of this class, all of which are approved by the regulatory agencies for the treatment of osteoporosis in men. The effects of bisphosphonates on BMD and bone turnover appear to be similar between men and women (48).
Denosumab
By binding to nuclear factor-kappa beta activating receptor-ligand (RANKL), denosumab prevents the interaction between RANKL, a powerful bone-resorbing cytokine, to its receptor RANK on osteoclasts. This results in a powerful inhibition of these cells and thus an antiresorptive effect (55).
Teriparatide
Teriparatide (PTH 1-34) comprises the initial 34 aminoacids of the 84-aminoacid PTH molecule. Insight into the therapeutic potential of PTH came from the observation that PTH, when administered intermittently and in low doses, stimulates bone formation. Thus, it is an osteoanabolic agent (60-62).
Abaloparatide
Abaloparatide is an analog of PTHrP, designed to maximize its interaction with the configuration of the PTH/PTHrP receptor that favors anabolic activity (67).
Safety of teriparatide and abaloparatide
The US Food and Drug Administration (FDA) has removed the boxed warning for both teriparatide and abaloparatide with regard to osteosarcoma and to the duration of use. This recommendation is based upon abundant surveillance data for teriparatide that did not show any oncogenic signals in human subjects after over a decade of careful monitoring (69,70).
Testosterone
Hypogonadism is a major etiology of osteoporosis in men. Testosterone deficiency is known to reduce BMD and increase the risk of fractures in men (18,22,25), which would justify its use in hypogonadal patients with osteoporosis. Testosterone replacement increases BMD, reduces bone turnover markers, and improves bone strength in men with hypogonadism (71-73). On the other hand, its use in the elderly with normal serum testosterone levels did not change BMD (74). Data regarding the effectiveness of testosterone treatment in fracture reduction are limited (75).
The Endocrine Society guidelines for male osteoporosis recommend testosterone replacement in hypogonadal patients (testosterone levels below 200 ng/mL in at least 2 measurements) who are symptomatic or who have known causes of hypogonadism (e.g. pituitary or testicular disorder) if there are no contraindications. However, testosterone is not the first-line therapy for hypogonadal men who are at high risk of fractures. Rather, an approved medication for osteoporosis is recommended and should be associated with testosterone therapy if there is a formal indication for testosterone replacement. Also, if there is a contraindication to an approved agent for osteoporosis in patients at high risk of fractures and testosterone levels below 200 ng/dL, testosterone therapy may be an alternative even with no standard indication for testosterone replacement (36).
Romosozumab
Romosozumab, an antisclerostin antibody, was developed to block the effects of sclerostin, a regulator of the Wnt bone formation signaling pathway. By blocking sclerostin, romosozumab was designed to be an osteoanabolic agent. Indeed, it is. However, another effect of romosozumab is as an antiresorptive agent. This mechanism of action is unique in that it is a dual-action drug, namely increasing bone formation and inhibiting bone resorption.
*Selection of initial therapy
*Monitoring therapy
In conclusion, this review summarizes the most recent data on the epidemiology, pathophysiology, etiology, diagnosis, and treatment of male osteoporosis. Despite a frequent condition, male osteoporosis is still underappreciated by physicians, with less than 20% of men being treated, even considering those with previous fractures. With the increase in life expectancy, osteoporosis has become more prevalent in men and its main outcome, namely fracture, underscores a major health burden in this population, in addition to remarkable costs for health systems around the world. Thus, it is urgent to increase awareness of male osteoporosis, reducing undertreatment and improving care for this population.
