Bone Loss and Fractures in Patients on Androgen Deprivation Therapy


the initial hypothesis. As a result, today we are seeing the emergence of complications from long-term ADT that were previously unknown because they were found only in long-term survivors of metastatic prostate cancer. The loss of bone mineral mass is one of the most important complications related to ADT.


During adulthood, bone tissue is subjected to a continuous remodelling process based on co-ordinated bone formation and resorption, which are mediated by the actions of osteoblasts and osteoclasts, respectively. The function of osteoclasts is regulated by various factors, such as the ligand receptor activator of nuclear factor-κB (RANK) and osteoprotegerin (OPG).7


The binding of RANK to its ligand (RANKL) leads


to the activation of a signal transduction pathway that mediates the formation and survival of osteoclasts, stimulating their function. Conversely, the binding of OPG to RANKL leads to the inhibition of bone resorption mediated by osteoclasts. Thus, bone mineral density (BMD) is the result of a complex series of balances at the cellular (osteoblast–osteoclast) and molecular (RANKL–OPG) levels.


The physiology of the bone remodelling process, mediated by multiple cytokines and hormones, explains why patients receiving ADT may have a decreased bone mineral mass. Oestrogens inhibit bone resorption, whereas androgens promote bone formation. Alteration of the balance between these mechanisms as a result of menopausal status, treatment with aromatase inhibitors in breast cancer patients or ADT in prostate cancer patients leads to an increased risk of bone loss.


The main objective of the present review is to provide information about the importance of bone loss resulting from ADT, as well as its incidence, prevalence and known risk factors and to review the scientific knowledge currently available. We also systematically review the state-of-the-art diagnostic and therapeutic manoeuvres (both pharmacological and non-pharmacological) available for handling this situation in prostate cancer patients receiving ADT.


Clinical Impact of Bone Mass Loss A bone fracture in an oncology patient represents a stressful situation that can lead to pain, a need for surgery or radiation therapy, bed rest and a general clear and abrupt decline in quality of life. Not all fractures have the same impact; it depends on the fracture location. Although fractures of the distal skeleton have a small impact and a low risk of associated mortality, multiple vertebral fractures can lead to restrictive respiratory failure and severe kyphosis. Sometimes, the event can be catastrophic for the patient and his or her caregivers, such as with hip fracture, which is associated with a significant mortality risk in male patients over 60 years with or without prostate cancer, as reported in a study based on nearly 4,000 patients.8


This


study and another study showed that mortality rates because of hip fracture were significantly higher in men than in women.8,9


Moreover,


the occurrence of a bone fracture at any site in patients with prostate cancer over the course of ADT is associated with a statistically significant decrease in overall survival.10


Thus, prevention of bone


fractures in these patients is important because it has an impact on overall survival.


The risk of new osteoporotic fractures during ADT increases with the duration of treatment. This phenomenon was highlighted by Daniell in his study published in 1997, which showed that the cumulative incidence of fracture reached almost 50 % nine years after an


EUROPEAN UROLOGICAL REVIEW


The WHO recently proposed a new instrument for the assessment of fracture risk. It is called the Fracture Risk Assessment Tool (FRAX®) and it calculates the patient’s osteoporotic fracture risk based on a series of clinical and epidemiological characteristics (age, sex, body mass index, smoking habit and others). FRAX was used in a cohort of 363 prostate cancer patients receiving ADT to estimate the risk of fracture. The results show that, without using DXA data, age is a crucial predictor that discriminates between patients with a high and low risk of fracture (with a cut-off at 70 years of age) and the incorporation of DXA adjusted the fracture risk estimation to a lower age.17


99


Table 1: World Health Organization Definition of Osteoporosis and Osteopenia According to T-score


Stage Normal


Osteopenia Osteoporosis


Severe osteoporosis orchiectomy was performed.3


T-score Value >-1


-1, -2.5 <-2.5


<-2.5 + fragility fracture Other clinical studies11 and three large


population-based studies have more clearly confirmed the increased risk of osteoporotic fracture in patients during ADT12–14


and its relation


to the number of LHRH analogue doses received during the first 12 months of treatment.12,14


Bone Mass Loss and Fracture Risk Quantification


Osteoporosis is a bone metabolic disorder characterised by the loss of bone mass and micro-architectural deterioration of bone tissue. Dual-energy X-ray absorptiometry (DXA) is the method of choice for quantifying bone loss. It was first recommended in 1994 by the US Food and Drug Administration (FDA) as the best method for this determination. Bone mass measurement provides two scores: the T-score, which quantifies the loss of bone mass in terms of standard deviations in relation to the normal estimated mass for a young adult; and the Z-score, which compares the result with the estimated normal mass for a person of the same age, sex and race. The Z-score is used in clinical practice to quantify the relative risk of fracture. According to T-score results, the World Health Organization (WHO)15


developed a qualitative classification system comprising four groups (see Table 1).


It is important to note that in the case of patients with bone metastatic prostate cancer, the bone location where the DXA measurement is conducted must be free of metastatic involvement. The International Society for Clinical Densitometry recommends that bone mass measurements should be performed at the femoral neck and lumbar vertebrae and in selected cases only, at the distal radius. However, the latter was found to be the most sensitive location for diagnosing osteoporosis in a recent study of prostate cancer patients by our group.16


In this study, osteoporosis was diagnosed in 30 % of patients when the bone mass measurement was performed at the distal radius, whereas in the same patients, measurements in lumbar vertebrae or the femoral neck diagnosed osteoporosis in 20 and 23 % of the patients, respectively. In addition, patients with prostate cancer are generally of advanced age and may have vertebral osteophytosis, aortic calcifications or degenerative pelvic bone problems. For all these reasons, we recommend estimating BMD in prostate cancer patients at the distal radius in addition to the locations recommended by the WHO (lumbar spine and femoral neck).


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