A systematic review and meta-analysis of bone metabolism in prostate adenocarcinoma

Prostate cancer (PCa) is the most common cancer in men in many Western countries and is the second leading cause of cancer death in men [1]. PCa is characterized by its propensity for bone metastases which occur in more than 80% of patients with advanced prostate cancer [2, 3]. Typical metastasis sites include the spine, pelvis and rib cage[4]. The median survival time of patients with PCa is approximately three years after the development of bone metastases, and during this period, patients are at risk of pain, hypercalcaemia, fracture and spinal cord compression [5].

Another feature of patients with PCa is bone loss and, in a more advanced period, osteoporosis. Antihormonal therapy used to inhibit the disease progression or prevent its recurrence can lead to changes in bone metabolism, resulting in the loss of bone mineral density (BMD) since this therapy depletes circulating levels of oestrogens and androgens that maintain bone mass through the suppression of bone reabsorption and promotion of bone formation [6]. These pathological changes are known as cancer treatment-induced bone loss (CTIBL). However, patients with prostate cancer typically have low bone mineral density (BMD) even before receiving hormone therapy as a result of age, underlying disease, or other co-morbidities [7].

Bone mass loss and osteoporosis may cause an increased risk of fractures due to a reduction in bone volume and microarchitectural deterioration. The WHO expert committee defines osteoporosis as a hip bone mineral density level (dual x-ray absorptiometry) of more than 2.5 SD below the mean for young, white, adult men (with a t-score of at least - 2.5 SD) in men age 65 years and older and in men from 50 to 64 years of age if other risk factors for fracture are presented [8]. The most significant complications of osteoporosis are fractures of the hip, forearm, and vertebrae. The occurrence of fractures significantly correlate with shorter survival in men with prostate cancer. When fracture history was evaluated, the median overall survival time was 39 months longer in men without a history of skeletal fracture. Therefore, a better understanding of the magnitude and prevalence of bone loss in these patients is critical [9, 10].

The objective of this review is to determine the incidence of bone loss and osteoporosis in patients with PCa who are or are not treated with hormone therapy.

An extensive body of literature reports on the association between androgen deprivation therapy and the incidence of osteoporosis. All the five studies that we identified, and that met the inclusion criteria, indicated a positive association between ADT and osteoporosis. In relation to fractures, all four of the identified studies indicated a positive association between ADT and the incidence of fractures. Furthermore, the association persisted and remained statistically significant across a number of stratified analyses that explored clinical and study quality factors.

Observational primary studies usually cannot prove causality. However, the studies in this review presented an appropriate temporal relationship; the androgen deprivation therapy and the diagnosis of prostate cancer diagnosis preceded the incidence of osteoporosis and fractures in all of the studies. Furthermore, androgen deprivation therapy depletes the circulating levels of oestrogens and androgens that maintain bone mass through suppression of bone reabsorption and promotion of bone formation [6]. These facts impart biological plausibility to our findings on the association between PCa and ADT with osteoporosis and fractures as shown by the forests plots (Figure 3A, 3B and 4).

The lack of adjustment for the presence of metastasis (only one study adjusted for this factor), calcium ingestion (no studies) and genetic predisposition (no studies) must be considered as a limitation of our study. The presence of metastasis, a low calcium ingestion and patients with history of osteoporosis in the family had a higher risk of osteopenia, osteoporosis and fractures.

It is estimated that two million men are affected by osteoporosis in the United States. Although men experience a gradual age-related loss of BMD of 7 to 12% per decade beginning at age 30, primary male osteoporosis is not common [42]. Most men who have clinically significant osteoporosis are older than 70 years of age and have risk factors that contribute to decreased bone mineralization, such as hypogonadism, thyroid and parathyroid disorders, glucocorticoid excess, alcoholism, osteomalacia, and malignancy [43]. The relationship between decreased BMD and ADT is well established. Androgen suppression reduces BMD approximately 3% to 7% per year [44]. Recent reports have demonstrated that men who have prostate cancer and are receiving ADT have BMD measurements from 6.5% to 17.3% lower than men who are not treated with ADT [7]. One study reported that spinal and femoral BMD values were 1.7% and 5.2% less after two years and 14% and 28% less after 10 years of ADT, respectively, as compared to age-matched control subjects [24].

Although some studies defend the idea that PCa patients (without ADT) have lower levels of BMD and higher rates of osteoporosis, we were not able to verify this finding in our study. In fact, patients with prostate cancer showed similar levels of BMD and lower rates of osteoporosis when compared with healthy controls. Assessed individually, three studies showed similar levels of BMD between PCa patients and healthy controls [21, 24, 37], one showed higher levels for the PCa group [12] and one showed lower levels [18]. With respect to osteoporosis, all studies showed lower rates in the PCa group as compared to healthy controls [12, 21]. One potential explanation for these findings is the highly debated association of a high endogenous androgen levels with the risk of prostate cancer, which may potentially explain the higher BMD seen in patients with PCa before they receive ADT as compared to normal men [45]. We were unable to evaluate this hypothesis in our study because only two of the evaluated studies had data on testosterone levels. Nevertheless, the prevalence of osteoporosis in man with PCa cannot be neglected.

Wei et al[39] found that 63% of patients who had hormone-naive prostate cancer had osteopenia or osteoporosis. In a larger study, Smith et al[33] demonstrated that 34% prostate cancer patients without exposure to ADT had dual-energy x-ray absorptiometry (DEXA) criteria for osteopenia or osteoporosis. Conde et al[17] reported a high prevalence of osteopenia (73.5%) and osteoporosis (17.6%) in 34 men who had non metastatic, hormone-naive prostate cancer. We could see that prostate cancer and ADT are strongly associated with bone metabolism modifications and, in these studies, advanced age, lower body mass index, and elevated prostate specific antigen levels correlated significantly with decreased BMD.

Fractures are associated with substantial morbidity and mortality. Men who experience hip fractures suffer greater impairment and have a higher rate of fracture-related mortality than women [46]. Approximately 20% to 30% of hip fractures occur in men, and 50% to 60% of men die within one year of the fracture [47]. The detrimental association between fracture and mortality extends to men who have prostate cancer. Oefelein and colleagues identified a negative association between skeletal fracture and overall survival in 195 prostate cancer patients treated with chronic ADT [9].

The bone mass of a normal adult is the outcome of a dynamic equilibrium between bone formation and bone resorption. The latter step is regulated by a family of proteins that include receptor activator of nuclear factor k-Β (RANK), RANK ligand (RANKL) and osteoprotegerin (OPG). Binding of RANKL to RANK on the surfaces of osteoclast precursors will trigger maturation, activation, and prolonged survival of these cells. Thus, RANKL promotes bone resorption. Vitamin D, parathyroid hormone, tumour necrosis factor-α (TNF-α), activated T-cells, and glucocorticoid therapy all increase this ratio, promoting bone resorption. Estrogen deficiency states produce osteoporosis because normal levels of 17β-estradiol inhibit RANKL production and stimulate OPG. Testosterone stimulates osteoblasts, inhibits the apoptosis of both osteoblasts and osteoclasts, and is a precursor of estrogen via aromatization; its net effect is to stimulate bone formation. In males under ADT, both testosterone and estrogen levels fall, shifting the balance of bone turnover toward resorption [48]. ADT does not have a significant impact on serum calcium, 25-hydroxyvitamin D, or PTH, but epidemiological studies have suggested that high levels of calcium intake may suppress PTH and ultimately 1,25-dihydroxyvitamin D and associated with increased risk of prostate cancer [49].

Current American Society of Clinical Oncology (ASCO) guidelines and expert panels suggest that patients under ADT with clinically significant bone loss should receive bisphosphonates, regardless of hormonal and metastatic status, and preclinical and clinical data show that bisphosphonates can also prevent and treat CTILB and may inhibit malignant bone disease development in patients with early stage disease [7, 10].