Treatment-related osteoporosis in men with prostate cancer

Osteoporosis is an important complication of androgen-deprivation therapy (ADT) for prostate cancer. ADT by either bilateral orchiectomies or treatment with a gonadotropin-releasing hormone (GnRH) agonist decreases bone mineral density (BMD) and increases the risk of fracture. Prospective data about treatment or prevention of osteoporosis in men with prostate cancer are limited. Supplemental calcium and vitamin D are recommended. Additional therapy may be warranted for men with osteoporosis or fractures. Intravenous pamidronate prevents bone loss in the hip and spine during ADT. Intravenous zoledronic acid not only prevents bone loss but also increases BMD. Alendronate is approved to treatmen with osteoporosis although the efficacy of alendronate or other oral bisphosphonates has not been evaluated during ADT. Additional prospective studies are needed to evaluate the long-term effects of bisphosphonates and other the rapies on fracture risk and disease-related outcomes.     

Bone loss after initiation of androgen deprivation therapy in patients with prostate cancer

CONTEXT: Although androgen deprivation therapy (ADT) for prostate cancer is associated with bone loss, little is known about when this bone loss occurs. OBJECTIVE: We postulated that men on ADT would experience the greatest bone loss acutely after initiation of ADT. DESIGN AND SETTING: We conducted a 12-month prospective study at an academic medical center. PATIENTS OR OTHER PARTICIPANTS: We studied 152 men with prostate cancer (30 with acute ADT, < 6 months; 50 with chronic ADT, > or = 6 months; and 72 with no ADT) and 43 healthy age-matched controls. MAIN OUTCOME MEASURES: We assessed bone mineral density (BMD) of the hip, wrist, total body, and spine; body composition; and markers of bone turnover. RESULTS: After 12 months, men receiving acute ADT had a significant reduction in BMD of 2.5 +/- 0.6% at the total hip, 2.4 +/- 1.0% at the trochanter, 2.6 +/- 0.5% at the total radius, 3.3 +/- 0.5% at the total body, and 4.0 +/- 1.5% at the posteroanterior spine (all P < 0.05). Men with chronic ADT had a 2.0 +/- 0.6% reduction in BMD at the total radius (P < 0.05). Healthy controls and men with prostate cancer not receiving ADT had no significant reduction in BMD. Both use and duration of ADT were associated with change in bone mass at the hip (P < 0.05). Men receiving acute ADT had a 10.4 +/- 1.7% increase in total body fat and a 3.5 +/- 0.5% reduction in total body lean mass at 12 months, whereas body composition did not change in men with prostate cancer on chronic ADT or in healthy controls (P < 0.05). Markers of bone formation and resorption were elevated in men receiving acute ADT after 6 and 12 months compared with the other men with prostate cancer and controls (P < 0.05). Men in the highest tertile of bone turnover markers at 6 months had the greatest loss of bone density at 12 months. CONCLUSIONS: Men with prostate cancer who are initiating ADT have a 5- to 10-fold increased loss of bone density at multiple skeletal sites compared with either healthy controls or men with prostate cancer who are not on ADT, placing them at increased risk of fracture. Bone loss is maximal in the first year after initiation of ADT, suggesting initiation of early preventive therapy.     

Bone health in men with prostate cancer: diagnostic and therapeutic considerations

With current treatments, men usually survive many years after being diagnosed with prostate cancer. However, the systemic effects of prostate cancer and therapies such as androgen deprivation therapy (ADT) can undermine skeletal integrity, resulting in skeletal complications that may erode quality of life (QOL). Prostate cancer patients are at risk for fractures from cancer treatment-induced bone loss. In addition, they are also at risk for pathologic fractures, severe bone pain, and other sequelae from bone metastases, which almost invariably occur during the progression of prostate cancer. This review investigates the incidence and pathophysiology of bone loss and skeletal morbidity in prostate cancer patients and reviews available treatment options for maintaining skeletal health throughout the continuum of care for these patients. Several supportive interventions are available to prevent generalized and localized bone loss, including calcium and vitamin D supplements and bisphosphonates. Oral calcium and vitamin D supplementation alone, however, appears to be insufficient to prevent bone loss during ADT. New generation bisphosphonates such as zoledronic acid can prevent bone loss for patients on ADT and can reduce skeletal morbidity for those with bone metastases.     

What is the role of alternative biomarkers for coronary heart disease?

Adverse effects of androgen deprivation therapy (ADT) are a consequence of the induced sex steroid deficiency. ADT increases fat mass leading to insulin resistance and diabetes, and accelerates bone loss causing increased fracture risk. Given the high prevalence of cardiovascular disease and reduced bone density in ADT‐naïve men with prostate cancer, the benefits of ADT have to be carefully weighed against its side effects, especially as a diagnosis of prostate cancer does not alter the life expectancy for most men. Men commencing ADT should be counselled about and be carefully monitored for these and other ADT‐induced complications, which include fatigue, sexual dysfunction, hot flushes and anaemia. ADT‐associated side effects should be prevented and treated in order that ADT‐induced toxicity does not outweigh its benefits. Future clinical trials are needed: first, to better define the effects of ADT on survival in men with localized prostate cancer or with biochemical prostate‐specific antigen recurrence; second, to delineate ADT‐associated harm, especially with respect to cardiovascular events and fractures; and third, to test the efficacy of interventions designed to minimize ADT‐related adverse outcomes. Such information will be essential to better quantify the risk‐benefit ratio of ADT in the individual man with prostate cancer.     

Bone loss in prostate cancer: evaluation, treatment and prevention

Modern medicine offers multiple treatment options to prolong the survival of patients with prostate cancer. However, in the absence of adequate supportive care, the systemic effects of prostate cancer and therapies such as androgen deprivation therapy (ADT) can undermine skeletal integrity, resulting in skeletal complications. Skeletal morbidity contributes to the erosion in quality of life in patients with prostate cancer. These patients are at risk for fractures from cancer treatment-induced bone loss and, later on, pathologic fractures from bone metastases, which may occur during the progression of prostate cancer. Several supportive care options are available to prevent generalized and focal bone loss, including calcium and vitamin D supplements and bisphosphonates. Oral calcium and vitamin D supplementation alone, however, appears to be insufficient to prevent bone loss during ADT. Bisphosphonates may be beneficial in preventing bone loss and eventually reducing skeletal morbidity due to prostate cancer and ADT.     

Prostate cancer, osteoporosis and fracture risk

Prostate cancer is often treated with androgen deprivation therapy (ADT). Although this treatment is effective the associated hypogonadism causes accelerated bone loss, osteoporosis and increased fracture risk in men with prostate cancer, even in the absence of bone metastases. In addition to the negative effects of ADT on bone metabolism, men with prostate cancer are at increased risk of osteoporosis due to advanced age, poor nutrition and vitamin D deficiency. Some treatments for prostate cancer avoid this side effect and these are discussed, together with treatment strategies to minimise the impact of ADT on bone health.     

Clinical Question: What is the best approach to managing glucocorticoid‐induced osteoporosis?

Glucocorticoid-induced osteoporosis is common, and the resulting fractures cause significant morbidity and mortality. Rapid bone loss and increased fracture risk occur soon after the initiation of glucocorticoid therapy and are dose dependent. The increase in fracture risk is partly independent of bone mineral density, probably as a result of changes in bone material properties and increased risk of falling. Fracture risk can be assessed using the FRAX algorithm, although risk may be underestimated in patients taking higher doses of glucocorticoids. Because of the rapidity of bone loss and increase in fracture risk after the start of glucocorticoid therapy, primary prevention should be advised in high-risk individuals, for example older women and men, individuals with a previous fracture history and those with low bone mineral density. Bisphosphonates are the front-line choice for the prevention of fracture in the majority of glucocorticoid-treated patients, with teriparatide as a second-line option. Calcium and vitamin D supplements should be co-prescribed unless there is evidence of an adequate dietary calcium intake and vitamin D status.     

Male osteoporosis-what are the causes,diagnostic challenges,and management

Osteoporosis is underrecognized and undertreated in men, even though up to 25% of fractures in patients over the age of 50 years occur in men. Men develop osteoporosis with normal aging and accumulation of comorbidities that cause bone loss. Secondary causes of bone loss may be found in up to 60% of men with osteoporosis. Mortality in men who experience major fragility fracture is greater than in women. Diagnosis of osteoporosis in men is similar to women, based on low-trauma or fragility fractures, and/or bone mineral density dual-energy X-ray absorptiometry (DXA) T-scores at or below ?2.5. Because most clinical trials with osteoporosis drugs in men were based on bone density endpoints, not fracture reduction, the antifracture efficacy of approved treatments in men is not as well documented as that in women. Men at a high risk of fracture should be offered treatment to reduce future fractures.     

The management of secondary osteoporosis

Secondary osteoporosis is common among patients being evaluated for osteoporosis. All men and premenopausal women with unexplained bone loss or a history of a fragility fracture should undergo a work-up for secondary osteoporosis. Also, postmenopausal women with risk factors for secondary osteoporosis should be carefully evaluated. The evaluation should include a thorough history, physical examination, bone mineral density testing, and laboratory testing. While there is no consensus for a cost-effective laboratory evaluation, some recommendations include: 25-hydroxyvitamin D, parathyroid hormone (PTH), serum and urine calcium, phosphate, creatinine, liver function tests, a complete blood count, testosterone in men, and thyroid-stimulating hormone. After a thorough review of the evaluation for secondary osteoporosis, this chapter reviews the pathophysiology and treatment of secondary osteoporotic disorders, including vitamin D insufficiency, osteomalacia, the osteoporosis of erosive inflammatory arthritis, ankylosing spondylitis, systemic lupus erythematosus, and osteoporosis related to anti-androgenic therapy for prostate cancer and aromatase inhibitor therapy for breast cancer. Physicians have a significant responsibility to evaluate and treat the underlying medical problem that is the cause of secondary osteoporosis and to optimize bone health in the individual patient.     

Osteoporosis in men

With the aging of the population, there is a growing recognition that osteoporosis and fractures in men are a significant public health problem, and both hip and vertebral fractures are associated with increased morbidity and mortality in men. Osteoporosis in men is a heterogeneous clinical entity: whereas most men experience bone loss with aging, some men develop osteoporosis at a relatively young age, often for unexplained reasons (idiopathic osteoporosis). Declining sex steroid levels and other hormonal changes likely contribute to age-related bone loss, as do impairments in osteoblast number and/or activity. Secondary causes of osteoporosis also play a significant role in pathogenesis. Although there is ongoing controversy regarding whether osteoporosis in men should be diagnosed based on female- or male-specific reference ranges (because some evidence indicates that the risk of fracture is similar in women and men for a given level of bone mineral density), a diagnosis of osteoporosis in men is generally made based on male-specific reference ranges. Treatment consists both of nonpharmacological (lifestyle factors, calcium and vitamin D supplementation) and pharmacological (most commonly bisphosphonates or PTH) approaches, with efficacy similar to that seen in women. Increasing awareness of osteoporosis in men among physicians and the lay public is critical for the prevention of fractures in our aging male population.     

Selection of individuals for prevention of fractures due to bone fragility.

Most patients with fractures go untreated because of the lack of awareness of osteoporosis. Treatment is indicated for women and men with osteoporosis and women and men with fractures with either osteoporosis or osteopenia because (a) fractures increase morbidity and mortality, (b) the burden of fractures is increasing because longevity is increasing, and (c) bone loss accelerates, rather than decelerates in old age. The indication for drug therapy is less clear in women or men with osteopenia because drugs have not been proved to reduce fracture risk in this group. There is no evidence that treating individuals with only risk factors reduces the fracture rate. Screening has not been shown to reduce the burden of fractures. Altering the bone mineral density by a few percent in the population is likely to reduce the number of fractures, but how this can be achieved is unknown. The rigorously investigated drugs reducing the spine fracture rate are alendronate, raloxifene and risedronate. Calcium and vitamin D reduce hip fractures in nursing home residents but not community-dwellers. In the community, only alendronate and risedronate have been reported to reduce hip fractures in randomized trials. The evidence for hormone replacement therapy is less satisfactory. It is likely to reduce the number of spinal fractures, but its role in hip fracture prevention is uncertain. Only alendronate has been reported to reduce spine fractures in men with osteoporosis. Evidence for the use of other drugs (calcitonin, fluoride, anabolic steroids and active vitamin D metabolites) in women or men is insufficient to justify their use.     

The effect of vitamin D on bone and osteoporosis

The main effect of the active vitamin D metabolite 1,25(OH)2D is to stimulate the absorption of calcium from the gut. The consequences of vitamin D deficiency are secondary hyperparathyroidism and bone loss, leading to osteoporosis and fractures, mineralization defects, which may lead to osteomalacia in the long term, and muscle weakness, causing falls and fractures. Vitamin D status is related to bone mineral density and bone turnover. Vitamin D supplementation may decrease bone turnover and increase bone mineral density. Several randomized placebo-controlled trials with vitamin D and calcium showed a significant decrease in fracture incidence. However, very high doses of vitamin D once per year may have adverse effects. When patients with osteoporosis are treated with a bisphosphonate, they should receive a vitamin D and calcium supplement unless the patient is vitamin D replete. These subjects are discussed in detail in this review. Finally, the knowledge gaps and research agenda are discussed.     

Wirkung von Vitamin D auf die Muskulatur im Rahmen der Osteoporose

A successful prevention strategy for fractures in the elderly should not be limited to an improvement in bone mineral density. Equally important is the prevention of falls. Thus, 90% of fractures in the elderly are associated with a fall and 30% of all ambulatory, and 50% of institutionalized elderly age 65 years and older fall at least once a year. Fall incidence increases 10% per decade thereafter. According to recent studies, vitamin D and calcium supplementation may be a promising treatment strategy targeting both bone mineral density, as well as muscle strength and the risk of falling. The protective effect of vitamin D on fractures has been attributed to the established moderate benefit of vitamin D on bone mineral density. However, an alternative explanation might be that vitamin D affects factors directly related to muscle strength, thus, reducing fracture risk through improved function and fall prevention, in addition to its benefits on calcium homeostasis.     

Impact of GHBP interference on estimates of GH and GH pharmacokinetics

BACKGROUND: Prostate cancer (PCa) is one of the most common cancers in men and has an increasing incidence. In 1999, 37 000 men died from PCa in the USA. Androgen deprivation therapy (ADT) with GnRH agonists is frequently employed in the treatment of recurrent and metastatic PCa by inducing medical castration, rendering these men hypogonadal. Because hypogonadism in men is associated with a wide range of complications, we attempted to determine the effects of long-term ADT in men with PCa. METHODS: We conducted a cross-sectional study at a tertiary care centre to determine the effect of ADT on lean body mass (LBM), muscle strength, bone mineral density (BMD), sexual function, and quality of life (QOL) in men with PCa. Three groups of men were enrolled: (1) 20 men with PCa who were undergoing medical castration with GnRH agonists for at least 12 months prior to the onset of the study (ADT group); (2) 18 age-matched men with nonmetastatic PCa who were post prostatectomy and/or radiotherapy but had not yet undergone ADT (non-ADT group); and (3) 20 age-matched normal men who were healthy and ambulatory (control group). RESULTS: Men on ADT had castrate levels of serum total testosterone (P < 0.0001), free testosterone (P < 0.0001) and oestradiol (P < 0.0001), which were significantly lower than in the other groups. Total body (P = 0.03) and lumbar spine (P < 0.0001) BMD was significantly lower in patients on ADT compared to other groups and was associated with higher levels of urinary N-telopeptide (P = 0.02). The ADT group had higher fat mass compared to the other groups (P = 0.0001) and significantly reduced upper body strength (P = 0.001) when compared to non-ADT patients. The ADT group had lower overall scores on Watt's Sexual Function Questionnaire compared to other groups (P = 0.0001), in particular a decrease in desire, arousal and frequency of spontaneous early morning erections. The ADT group also had lower overall QOL scores, resulting in significant limitation of physical function (P = 0.001), role limitation (P = 0.02) and perception of physical health (P = 0.004). CONCLUSIONS: This study suggests that osteoporosis, unfavourable body composition, sexual dysfunction and reduced quality of life are seen in patients receiving androgen deprivation therapy for at least 12 months. Longitudinal studies in this patient population will shed further light on the timing of the development and the extent of these complications. Meanwhile, this information will assist both physicians and patients with prostate cancer to make informed decisions regarding androgen deprivation therapy.     

Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis: 2001 update. American College of Rheumatology Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis

Glucocorticoid-induced bone loss should be prevented, and if present, should be treated (Table 2). Supplementation with calcium and vitamin D at a dosage of 800 IU/day, or an activated form of vitamin D (e.g., alfacalcidiol at 1 microg/day or calcitriol at 0.5 microg/day), should be offered to all patients receiving glucocorticoids, to restore normal calcium balance. This combination has been shown to maintain bone mass in patients receiving long-term low-to-medium-dose glucocorticoid therapy who have normal levels of gonadal hormones. However, while supplementation with calcium and vitamin D alone generally will not prevent bone loss in patients in whom medium-to-high-dose glucocorticoid therapy is being initiated, supplementation with calcium and an activated form of vitamin D will prevent bone loss. There are no data available to support any conclusion about the antifracture efficacy of the combination of calcium supplementation plus an activated form of vitamin D. Antiresorptive agents are effective in the treatment of glucocorticoid-induced bone loss. All of these agents either prevent bone loss or modestly increase lumbar spine bone mass and maintain hip bone mass. While there are no randomized controlled trials of prevention of glucocorticoid-induced bone loss or radiographic vertebral fracture outcomes with HRT or testosterone, patients receiving long-term glucocorticoid therapy who are hypogonadal should be offered HRT. The bisphosphonates are effective for both the prevention and the treatment of glucocorticoid-induced bone loss. Large studies have demonstrated that bisphosphonates also reduce the incidence of radiographic vertebral fractures in postmenopausal women with glucocorticoid-induced osteoporosis. Treatment with a bisphosphonate is recommended to prevent bone loss in all men and postmenopausal women in whom long-term glucocorticoid treatment at > or =5 mg/day is being initiated, as well as in men and postmenopausal women receiving long-term glucocorticoids in whom the BMD T-score at either the lumbar spine or the hip is below normal. While there is little information on the prevention or treatment of bone loss in premenopausal women, these women, too, may lose bone mass if they are being treated with glucocorticoids, so prevention of bone loss with antiresorptive agents should be considered. If bisphosphonate therapy is being considered for a premenopausal woman, she must be counseled regarding use of appropriate contraception. The therapies to prevent or treat glucocorticoid-induced bone loss should be continued as long as the patient is receiving glucocorticoids. Data from large studies of anabolic agents (e.g., PTH) and further studies of combination therapy in patients receiving glucocorticoids are eagerly awaited so additional options will be available for the prevention of this serious complication of glucocorticoid treatment.     

Prevention of osteoporosis in cardiac transplant recipients

Osteoporosis is a leading cause of pretransplant and posttransplant morbidity. The need for early detection by measuring bone mineral density, even before transplant, must be emphasized. Preventive measures are not comparable. The use of calcium and vitamin D supplements, although recommended, is inadequate for the prevention of bone loss and complications such as vertebral fractures. Bisphosphonates have been shown to attenuate the bone loss and reduce fractures associated with steroid-induced osteoporosis. Small studies in transplant recipients suggest similar results. Other preventive measures such as hormone replacement therapy are also helpful. There are limited data on the administration of nasal calcitonin in transplant recipients.     

Combination therapies on osteoporosis

Combination therapies of bisphosphonates with conjugated equine estrogen (CEE) , vitamin D or parathyroid hormone (PTH) on osteoporotics have been discussed. Combined therapy of bisphosphonate with CEE increased lumbar bone mineral density (LBMD) and femoral neck bone mineral density (FBMD) in elderly patients. Furthermore combination therapy of bisphosphonate with CEE reduced new vertebral fractures in elderly osteoporotics. Similarly combination therapy of bisphosphonate with vitamin D is also advantageous to the increase of LBMD and FBMD. It is likely that the merit of combination therapy is to increase not only the lumbar BMD, but also the femoral BMD, although monotherapy is only to increase lumbar BMD. In contrast to CEE vitamin D seems to assist the effect of bisphosphonate in non-respondent patients to bisphosphonate. However, combination therapy of bisphosphonate with PTH might be complex in reducing the effect of alendronate.     

Osteoporosis in Ankylosing Spondylitis

Osteoporosis (OP) is a frequent complication of ankylosing spondylitis (AS), even in early stages of the disease, and is associated with elevated levels of biochemical markers of bone turnover, proinflammatory cytokines, and acute-phase reactants. This suggests that systemic inflammatory mediators, such as interleukin-6 and tumor necrosis factor-α, may be involved. Various factors that conceivably work in conjunction with one another also cause bone loss in AS (eg, genetic polymorphisms of vitamin D, low levels of osteoprotegerin and sex steroid hormones, and impaired calcium and vitamin D absorption). Dual x-ray absorptiometry for assessing bone mineral density (BMD) has limitations in patients with AS because of unreliability of spinal measurements, particularly in advanced disease with new bone formation. Femoral neck BMD is reduced and correlates with increased risk of vertebral fractures. Hence, measurement of BMD at the femoral neck may provide the most accurate means of detecting osteopenia and OP and could assess fracture risk in AS patients. No guidelines are available for detection and treatment of OP in AS, and most patients are young men, who are less likely to be screened. The only evidence-based recommendation is that optimal control of disease activity in AS prevents bone loss. A recent study showed a beneficial effect of infliximab therapy on bone turnover markers and BMD in AS. Also, bisphosphonates may be useful in managing OP in AS.     

Prostate Cancer Survivorship: Prevention and Treatment of the Adverse Effects of Androgen Deprivation Therapy

BACKGROUND

More than one-third of the estimated 2 million prostate cancer survivors in the United States receive androgen deprivation therapy (ADT). This population of mostly older men is medically vulnerable to a variety of treatment-associated adverse effects.

MEASUREMENTS AND RESULTS

Androgen-deprivation therapy (ADT) causes loss of libido, vasomotor flushing, anemia, and fatigue. More recently, ADT has been shown to accelerate bone loss, increase fat mass, increase cholesterol and triglycerides, and decrease insulin sensitivity. Consistent with these adverse metabolic effects, ADT has also recently been associated with greater risks for fractures, diabetes and cardiovascular disease.

CONCLUSION

Primary care clinicians and patients should be aware of the potential benefits and harms of ADT. Screening and intervention to prevent treatment-related morbidity should be incorporated into the routine care of prostate cancer survivors. Evidence-based guidelines to prevent fractures, diabetes, and cardiovascular disease in prostate cancer survivors represent an important unmet need. We recommend the adapted use of established practice guidelines designed for the general population.