Osteoporosis is a common problem.  As a matter of fact, the World Health Organization has stated that osteoporosis is the most common disease in the Western Hemisphere.  This is a disease of the skeleton where bone breakdown is greater than the bone being built.

In 1990 30% of the 1.7 million hip fractures worldwide occurred in men.  By 2025 the total # of hip fractures in men will be similar to the current # reported by women.  The complications and death caused by hip fractures is 3 times higher in men than women.  The incidence of fractures in men is similar to that of women who are 5 to 7 years younger.  And it is fractures that are the critical factor—the ultimate goal is the prevention of fractures and their subsequent complications.

So why has this problem been ignored for so long in men?  Although osteoporosis has long been viewed as a woman’s problem, five studies suggest that the prevalence of spine fractures is similar in men and in women.  Somewhere between 10-20% of people over 65 suffer from vertebral fractures.  Two small study groups of men revealed higher than expected levels of osteoporosis.  One involving 103 men from 51-95 found 20% osteoporotic.  Another study showed even higher incidence in forearm studies.

Two factors contribute to men’s fractures:  a low peak BMD (bone mineral density) and/or excessive bone loss.  Peak bone mass is greater in men than women; peak density (amount of bone in the bone) is the same in men and women.  Remember that two types of bone exist:  trabecular and cortical.  Remember also that most fractures involving bone loss occur in trabecular bone.  Interestingly in men, Dr. E. Orwoll notes that between one half and two thirds of men with osteoporosis will have an identifiable cause such as alcohol or tobacco abuse or specific hormone abnormalities.  Dr. Orwoll also says that annual rates of bone loss in older men are about one third less than the loss in postmenopausal women.  It is not clear whether bone loss in men is mostly from accelerated bone resorption or depressed bone formation.

So what causes bone loss?  Interestingly, Dr. Ego Seeman says that there is increasing evidence that estrogen deficiency contributes to bone loss in men.  Again, remember that bone loss in women has long been attributed to declining estrogen levels in pre- and postmenopausal women.  It seems that testosterone contributes to the circulating levels of estrogen in men, and men with low estrogen levels may lose bones faster than men with higher circulating levels of estrogen.  Dr. Orwoll does not feel that it has been clearly demonstrated that lower levels of testosterone and estradiol levels in men cause osteoporosis in men although he does not that some studies seem to indicate as Dr. Seeman says that there is some correlation between lower levels of these hormones and BMD levels.  He also mentions that recent evidence suggests that both hormones may regulate cell death (thus increasing bone loss?).

BMD and FRACTURES

One of the problems with measuring the BMD of men and women is that the data to determine the “normal” data is determined from the bone density of young women.  The average bone mass in healthy young women is always lower than that observed in healthy young men.  So, few men are classified as osteoporotic (T score <-2.5) based on the “normal” data from young women.  Dr. Pols would like to see  BMD measurements reported in terms of absolute risk, so rather than just a T-score, a BMD report could integrate the age of the subject and the bone mass and then compute the risk of fracture over the next 5 to 10 years.  However, from the Rotterdam study, Dr. Pols reported that low BMD was demonstrated to be as strong a predictor of fracture in men as in women.

RISK FACTORS FOR OSTEOPOROSIS IN MEN

Risk factors for fractures include tobacco use, excessive alcohol intake, inactivity, leanness, low calcium intake, certain drugs such as corticosteroids, anticonvulsants, heparin and excessive thyroid replacement may cause bone loss.  But fractures may be the only reason a man seeks treatment.  Diseases such as multiple myeloma, adult-onset celiac disease, Cushing’s Syndrome, primary ayperpara thyroidism, idiopathic hypercalcicuria, mastocytosis and others should be considered when men have fractures.

Several studies show lower bone mass in smokers.  And studies out of the UC San Francisco of 1705 men showed that calcium potassium and lutein levels were independent predictors of osteoporosis.  Investigators there suggest that higher dietary intake of calcium, potassium and lutein may contribute to bone health in older men.

INCREASED PEAK BMD PREVENTS BONE LOSS=REDUCTION IN FRACTURES
10-30% of higher peak BMD’s may be achieved by performing vigorous exercise before puberty.  The effect of the increase calcium on bone mass in young men is unclear but evidence suggests girls have increased peak bone density and bone size with increased calcium.  Normal age of puberty onset with no tobacco use may result in higher peak BMD #'s.  Low body weight may also be a factor in lowering peak BMD.

As adults, we should not allow ourselves to become sedentary.  Maintaining our mobility and flexibility may help reduce falls.  Exercise may slow bone loss but probably won’t restore lost bone.  Additional calcium may slow bone loss but clinical trials in men have not been done to confirm this.  Avoidance of tobacco and excessive alcohol are reasonable approaches to prevention.

BISPHOSPHATES
Few proper trials have been done in men.  Of those one published by Orwall in the New England Journal of Medicine showed that alendronate does reduce spine fracture risk in men with osteoporosis when results were limited to those with BMD below –2.5SD.  The difference in spine fracture rates was statistically significant.  Non-vertebral fractures showed no differences.

One well done 2 year study of alendronate showed that men with T scores <-2.0 had increased BMD of the hip and spine.  Alendronate also reduced the risk of spine fracture.

ANDROGEN
Testosterone therapy might be considered in men with proven low levels of testosterone.  Androgen replacement in these men may increase muscle mass and strength, libido, bone mass and hair growth.  Testosterone treatment in older healthy men who have mildly lowered T levels has not been studied.  Judgment on the use of androgen treatment for osteoporosis in men needs formal clinical trials to determine if there is reduced risk of fracture that can be offset by increased risk of prostatic cancer.  One R&D department in a Japanese pharmaceutical company (Kaken Phar. Co) is working on a drug that binds with androgen thus having tissue selectivity and could have high potency for bone formation while having lower impact on prostate.  No large studies have been done on the safety of testosterone replacement nor are there any studies that demonstrate that testosterone replacement reduces the incidence of fracture.

PTH
A bone forming drug for men would be just as inviting as for women since this would increase BMD through new bone.  E. Orwoll of the Oregon Health Science at the University in Portland has done an 11 month study using rhPTH.  BMD decreased in 40% of the men who used the placebo.  Those receiving PTH had spine BMD increases of 5% or greater.  BMD was increased in men with normal and low levels of testosterone.

Another study simply followed 22 men with osteoporosis of unknown cause (not double blind or random and no real controls) for 23 months.  After PTH 14 took bisphosphate while 8 took no more medications.  Six months after PTH the men who took bisphosphate then had a further increase of 3% in spine studies, 6 men took PTH for 16 months and had increase of 7%.  Two men with no treatment had decreases of 5 to 6%.  This study needs to be tried under regular clinical trials with controlled, random participants of greater numbers however this small group suggest that PTH increased BMD in men and that the reversal of the effect may be prevented with subsequent bisphosphate therapy.

The Lilly Research Labs have been doing PTH trials on male and female rats.  The studies seem to indicate that PTH will be effective in restoring bone structure in males as well as females.

PTH UPDATE FOR WOMEN—Dr. John P. Bilezikian

Approval of PTH (to be known as Forteo) by the FDA is expected soon.  This will provide new options of treatment for women.  PTH will be the first approved treatment that actually stimulates bone formation to increase mass.  (Other available medications have inhibited bone breakdown.)

In double blind placebo controlled trials of PTH in osteoporotic men, Kurland reported 12 to 14% increases in lumbar spine BMD.  There was no change in the control group.  By 18 months of treatment, an increase in the femoral neck (hip) BMD reached significance.

In the Neer study on 1,637 postmenopausal women with prior vertebral fractures who took PTH along with daily calcium and Vitamin D experienced significant increases in vertebral, femoral and total body BMD.  There was 65-70% reduction in vertebral fractures, and reduction of nonvertebral fractures of 45%.  Higher dosages of the PTH increased BMD but the two dosages seemed to have similar effects on fracture risk.  The PTH was well tolerated. 

According to Dr. Bilezikian, some recent studies in small sample sizes of men seem to show similar effects on BMD but there were no fracture data.

Recent research from the Dempster group published in Journal of Bone and Min eral Research on bone biopsies in women and men treated with PTH showed significant increases in travecular connectivity density.  The architectural improvement suggests quality of bone with PTH is better.  So, PTH appears to improve quantity and quality.

Remaining Questions on PTH

Some potential downside and uncertainties exist.  PTH will be given daily by subcutaneous injections.  The treatment likely will be expensive.  Many questions remain about its use.  One involves optimal length of use.  Clinical trials lean toward a 2-year duration.  Another question is whether or not to use in conjunction with antiresorptives such as risedronate (Actonel) or alendronate (Fosamax) or to give these drugs after the PTH.  Some indications are that the BMD gains will be lost in a year if an antiresorptive is not given following the PTH.  Rapid loss of bone density following discontinuation was seen in the first small scale study of PTH in osteoporotic men.

The long-term safety of PTH has yet to be established with potential adverse effects including hypercalcemia and hypercalciuria.

Another question:  Who are the most appropriate candidates for this treatment?  Most likely PTH will be used in patients with more advanced osteoporosis particularly those who already have had osteoporotic fractures rather than those who are at risk by virtue of low BMD only.

SERMS

There are two interesting studies on selective estrogen receptor modulators (or SERMS).  Remember earlier it was mentioned that there is some question on the importance of estradial levels in men and bone loss, so there is increasing interest in the effect of SERMS on men.  One short-term (6 week) controlled trial of raloxifene (at  twice the FDA-approved dosage for women) vs placebo was tried with 43 men.  Another study fro the Mayo Clinic was a 6 month controlled trial of raolxifene on 50 older men.  From measuring markers of bone turnover and other chemicals, researchers felt that older men with higher levels of estradiol may not benefit from raloxifene, but they felt there were beneficial effects in men with low estradiol levels.  Additional studies of bone mass, fracture risk and adverse effects are needed to better determine the role of SERM usage in men.

STRONTIUM RANELATE

In France strontium ranelate, an oral agent that inhibits bone resorption and stimulates bone formation showed significant increases in trabecular bone in female mice.  Lesser increases in trabecular bone was shown in male mice.  There was increase of osteoblastic surface and decrease of bone resorption.  Clinical trials are under way on postmenopausal women.

SO WHERE DOES THIS TAKE US?

Osteoporosis in men has been an ignored health problem.  However, finally some progress has been made, but much more needs to be studied.  Information about effectiveness of drugs in spine fracture prevention is still limited.  Only two trials (as of October 2001) have been done in men, and no studies have been done regarding hip fracture and bisphospate or PTH.  There is no evidence that testosterone reduces fractures.  It is believed that testosterone increases BMD but the necessary randomized clinical trials have not been done.  The role of calcium supplements to prevent fractures in men is not known.

Remember the rates of death and complication in men with hip fractures is 3 times higher than in women.  There is still a long way to go in the study of osteoporosis in men but at least finally some studies are being done.

Drs Orwoll and Pols in a meeting of the International Bone and Mineral Society and the European Calcified Tissue Society in June, 2001 both mentioned important studies ongoing in this field.  Dr. Orwoll mentioned MrOS, a study which is funded by the National Institute of Health and will enroll over 600 men in the United States along with men from Hong Kong and Sweden for the next 5 years.  Dr. Pols mentioned the Rotterdam Study from the Netherlands where they are studying over 3000 men and nearly 5000 women.

So there are studies ongoing in this area involving larger numbers of men in controlled studies.

Options for management of osteoporosis continue to grow.  One challenge will be how to use the new drugs to best meet the individual’s needs.
 

SOURCES:

OSTEOPOROSIS in MEN by Douglas C. Bauer, MD reporting on the 1^st Joint Meeting of the International Bone and Mineral Society and the European Calcified Tissue Society, June , 2001.

OSTEOPOROSIS in MEN by Dr. Ego Seeman, Twenty-Third Annual Meeting of the American Society of Bone Mineral Research, October, 2001

PTH for Osteoporosis Treatment:  An Update by John P. Bilezikian, MD, Menopause Management, January/February 2002.