Osteoporosis in men has been categorized, classically, into three types: (1) Involutional or senile osteoporosis; (2) Idiopathic in middle aged males; and (3) Secondary osteoporosis. Up to 50%-65% of the diagnoses in male patients are secondary to metabolic diseases, toxic substances or iatrogenic side effects[24,27].
In men, testosterone plays a major role in bone metabolism, similar to the role of estrogens in females. Several studies have reported the importance of the estrogen receptor (ER)-alfa and aromatase inhibitors on the growth and development of pathological conditions of bone. Other authors have demonstrated the importance of the androgen receptor (AR) whose function is essential for male-type bone formation and remodeling, because promotes osteoblastic activity. Furthermore they showed that deficiency of AR has a essential effect on the expression of the receptor activator of NF-κB ligand (RANKL) gene, which encoding an osteoclastogenesis inducer.
Up to 70% of bone turnover and resorption appear to be modulated by estrogens and 30% by testosterone. Moreover both hormones are substantial in bone formation mechanisms.
Although hormonal changes in men are not so marked as in females, they are also important in the pathogenesis of osteoporosis. Sex-hormone binding globulin (SHBG) levels increase with aging in men. On the contrary, serum bio-available (or non-SHBG bound) estradiol and testosterone levels decrease with age. BMD is clearly related with steroid levels, especially with bio-available estradiol levels.
The trabecular and endosteal resorption in osteoporosis patients is not compensated by bone formation. The periosteal apposition, capital in the male bone metabolism, is directly related with bio-available levels of testosterone. A deficit in testosterone levels leads to bone loss and increases the risk of fracture[23,26].
The association between aging and serum SHBG levels remains unclear. Nevertheless, an inverse relation of insulin-like growth factor I (IGF-I) levels and SHBG levels has been widely proven. IGF-I directly inhibits SHBG production by liver cells.
Periosteal apposition, that compensates endosteal resorption, especially in men, is modulated not only by testosterone, but also by growth hormone (GH) and IGF-I levels.
An inadequate peak bone mass is involved in the pathogenesis of osteoporosis in males. Inherited factors such as gene regulation of steroids production, GH or IGF-I, are directly related with the peak bone mass. The lower the peak bone mass, the greater the possibility of developing an age-related osteoporosis.
Frequent causes of secondary osteoporosis are:
Hypogonadism: This is one of the most frequent etiologies of secondary osteoporosis in men. Studies carried out in nursing homes showed that, among geriatric individuals who had suffered a hip fracture, up to 66% had hormonal levels lower than the standard.
Other authors have documented a marked increase in the risk of suffering fragility fractures among patients with low levels of testosterone and estradiol. Moreover, these low levels of sexual hormones lead to muscle atrophy and total muscular mass decrease. Therefore, a hormonal deprivation on muscle function damages the defensive mechanism against falls, thus increasing the incidence of fractures in these individuals.
Nowadays, it is widely accepted that bone metabolism disorders in patients with low levels of estradiol can increase the risk of fractures[38,39]. This might be caused by a deficit of testosterone transformation into estradiol due to an aromatase enzyme dysfunction. There are several reports along these lines documenting severe male osteoporosis induced by mutations of the estrogen-receptor of the aromatase enzyme[40,41].
Low serum levels of vitamin D: Vitamin D plays a major role on bone health in all age groups. In younger individuals it contributes to achieving a good peak bone mass whereas in adults, lower levels of vitamin D lead to substantial losses in bone mass and subsequently to osteoporosis. Two sources of vitamin D are found in humans: (1) Epidermal synthesis of Vitamin D3 (colecalciferol) under sunlight influence (UV-B radiation); or (2) Absorption in the gastrointestinal tract, from the diet or nutritional supplements [in some countries certain food is supplemented with Vitamin D2 (ergocalciferol)]. Vitamin D is then metabolized in the liver into 25-hydroxivitamin D (25-(OH) D).
Vitamin D stimulates intestinal calcium absorption. Few food groups contain high concentrations of vitamin D: fatty fish, fish-liver oils (cod liver oil), and liver. Not all of them are available in all countries or they are not consumed regularly by the adult population. Moreover, certain foods such as milk, margarine, butter, orange juice and cereals are not regularly supplemented with Vitamin D in many countries, such as Spain. Therefore, daily requirements of Vitamin D are frequently insufficient in some regions[43,44]. Similarly, the substantial epidermal synthesis of Vitamin D in younger populations is reduced in the elderly. Curiously, in Spain, where the amount of sunlight radiation is high, the older population is usually poorly exposed to this radiation, and the synthesis of Vitamin D is even lower.
The European SENECA Study, carried out in 12 European countries, showed serum levels of 25 hydroxi-vitamin D lower than 30 ng/mL in 36% of the elderly population. In our country, a recent study also showed low levels of 25-hydroxyvitamin-D serum in elderly people, with a 95% sensibility to detect secondary hyperparathyroidism.
The presence of low levels of vitamin D in men over 65 years of age is very common. It has been considered that about 15% of male osteoporosis cases are caused by this deficiency. Several studies[49-51] have found a high prevalence of 25-hydroxyvitamin-D serum levels below 25 ng/mL in the population over 65 years of age (standard levels are above 35 ng/mL).
This has a major impact on bone metabolism. Firstly, a decrease in the intestinal absorption of calcium decreases the serum ionized calcium concentration. This gives way to an increased production of parathyroid hormone (PTH) which stimulates bone osteoclasts, releasing calcium into the bloodstream. PTH also increases renal resorption of calcium and renal excretion of phosphorus.
All these metabolic disorders, triggered by the vitamin D deficiency, lead to a significant increase of bone resorption and, consequently, to a decrease of BMD.
Our experience with 267 patients sustaining a hip fracture, with a mean age of 80.3 years, proved that 67% of them had vitamin D serum levels below 25 ng/mL at the time of admission. These results assert the high frequency of this deficiency in men with osteoporosis.
Poor calcium intake: The correct daily calcium intake is essential for bone metabolism. An intake below the recommended 1.200 mgrs per day is quite usual in the population over 65 years of age. This is directly linked with a low mineral bone density. If, as usual, it is also associated with low vitamin D serum levels, the negative consequences for the mineral metabolism and the health of the individuals are even greater.
Influence of tobacco: Among the toxic substances involved in the etiology of osteoporosis, tobacco plays a major role. Smokers have been found to have lower BMD and consequently a significantly higher risk of fragility fracture. Smoking is endemic within the Spanish population over 65. It should also be noted, that this harmful effect has usually been maintained for many years, in most cases since adolescence.
Alcohol: Alcohol is another toxic substance affecting BMD[54,55]. It is also quite well rooted in the Spanish population. A significant percentage of people in this country are regular drinkers, particularly men. A recent population study of a large, representative sample of the population aged 55 or more in Zaragoza (Spain) has documented that, among men, the proportion of heavy drinkers (WHO criteria) is 16.7%, in comparison to only 0.7% among women. Heavy drinking may lead to significant adverse effects, not only in the mineral metabolism, but also in the whole metabolic system. It might also be hypothesized that different rates of osteoporotic fractures in men and women are influenced by differences in alcohol consumption.
Coffee consumption: Contrary to what was classically thought, we now know that there is not enough evidence to link heavy coffee consumption with osteoporosis in men.
Hormonal treatments: Prostate cancer, a prevalent male disease, can be treated in some cases with androgenic suppression, which is a major risk factor for osteoporosis. In a recent study carried out by Adler, 33% of patients with prostate cancer who were treated with androgenic deprivation therapy, showed low BMD, fulfilling osteoporosis criteria in DXA scanning of their hip and spine.
Adler applied the new fracture prediction algorithm tool (FRAX) with corrected femoral neck T-score, reporting that 17% of these patients required treatment. Without any correction this percentage increased to 54% of the patients. In our experience with 87 patients undergoing hormonal treatment for prostate cancer for more than one year, and whose mean age was 78.3 years, 27.58% of them showed a BMD lower than 2.5 standard deviations in the DXA scanning.
Other causes: Other causes involved in the etiology of secondary osteoporosis in men are: (1) Anticonvulsant therapy; (2) Prolonged steroid therapies; (3) Patients with rheumatoid arthritis or ankylosing spondylitis; (4) Primary hyperparathyroidism; (5) Hepatic or renal disease; (6) Malabsorption syndromes; (7) Transplanted patients or those treated with immunomodulators; (8) Thyrotoxicosis; (9) Diabetes mellitus; (10) Hypercalciuria; and (11) Patients with human immunodeficiency virus (HIV). Overall we can say that there is no specific pathology affecting male bone metabolism, but various conditions or medical treatments can cause secondary osteoporosis. And these conditions may affect similarly individuals of both genders.