Osteoporosis Treatment May Benefit Breast Cancer Patients

“…tumor cells that have disseminated in bone provide growth factors activating the bone microenvironment, which in turn produces growth factors that feed tumor cells in a cycle of mutual cooperation.”

“When a plant goes to seed, its seeds are carried in all directions; but they can only live and grow if they fall on congenial soil.” – Stephen Paget. Lancet (1889).

The fascinating story of bisphosphonates started almost 50 years ago with the pioneer work of H Fleisch, a Swiss physician who found that plasma and urine contained inorganic pyrophosphate that inhibits calcium phosphate precipitation [1]. However, pyrophosphate had limited clinical application because of rapid hydrolysis after oral administration. G Russell joined Dr Fleisch's Medical Research Institute in Davos, Switzerland, and together they collaborated with D Francis, a chemist at Procter and Gamble, that led to the discovery of bisphosphonates that were shown to resist enzymatic hydrolysis but also turned out to be powerful inhibitors of bone resorption [2].

Chemically the bisphosphonates are synthetic compounds that resemble pyrophosphate, in which the P-O-P structure is replaced by a P-C-P bond that is resistant to chemical and enzymatic hydrolysis. The basic P-C-P structure can be modified at the two lateral chains on the carbon atom or by esterifying the phosphate groups, leading to unique members of the family with distinct effects on bone metabolism. The ability of the compound to bind to bone surface seems to be dependent on the P-C-P bond while the side chain in combination with the P-C-P bond defines ability to inhibit bone resorption.

The major biological effect of bisphosphonates is to reduce osteoclast numbers by inhibiting the recruitment of preosteoclasts and by promoting their apoptosis. During the 1990s, M Rogers and others within his group in Sheffield elucidated the molecular mechanisms of action of the bisphosphonates, and showed that nitrogen-containing bisphosphonates act as inhibitors of mevalonate metabolism resulting in inhibition of protein prenylation, the same pathway used by statins to block cholesterol synthesis [3].

The first clinical use of bisphosphonates taking advantage of their strong osteoclastic inhibitory activity was reported by G Russell and R Smith in patients with Paget's disease of bone [4]. However, it was not until the 1990s that the first clinical report on the efficacy of bisphosphonates on fracture prevention in osteoporosis using the first-generation compound, etidronate, was published [5], followed by several fracture prevention trials in postmenopausal osteoporosis using the more potent aminobisphosphonates alendronate [6] and risedronate [7]. The oncology field benefited from the bisphosphonates discovery during the same period, reporting clinical usefulness in malignancy-associated hypercalcemia in patients with solid tumors by intravenous (iv.) administration [8].

Perhaps the most fascinating development in oncology came from studies testing the ‘seed and soil’ hypothesis of S Paget first proposed in 1889 [9]. An Austrian physician by the name of E Fuchs had proposed a similar hypothesis 7 years earlier but was never credited with this discovery [10]. Nevertheless, after reviewing over 700 pathological reports of cancer patients, Paget speculated that tumor cells (seed) “can only live and grow if they fall on congenial soil.” In other words, tumor cells that have disseminated in bone provide growth factors activating the bone microenvironment, which in turn produces growth factors that feed tumor cells in a cycle of mutual cooperation [11]. The ‘seed and soil’ hypothesis is further supported by the recent discovery that tumor cells activate RANKL production [12]. RANKL activates osteoclast precursors into maturation and activation. Once osteoclasts are activated, osteolysis takes place, causing release of bone-derived TGF-β, IGF-1 and other cytokines in the bone microenvironment. These factors bind to cell surface receptors on tumor cells and promote their proliferation, facilitating the establishment and growth of metastatic breast cancer cells in the skeleton. By slowing down bone turnover, bisphosphonates have an immediate and potent effect on growth factors release from the bone micorenvironment and diminish the capacity of tumor cells to grow in bone [6,13]. The clinical translation of this mechanism of this was demonstrated in a landmark study published by Hortobagyi in 1996 that clearly demonstrated the beneficial effect of iv. administration of the amino-bisphosphonate pamidronate in established metastatic bone lesions of breast cancer [14]. Although these agents improved the patients’ quality of life, they had no significant benefit on their survival.

“We found that use of bisphosphonates was not only associated with a very strong reduction in the risk of developing bone metastases (approximately 50%) but also a very significant and similar benefit on overall and cancer-related survival.”

The logical next development was therefore to test the efficacy of these agents in the preventative setting to determine their potential efficacy not only in the development of skeletal metastases, but also on disease-free survival and overall survival. Much excitement came from a report by Diel et al. in 1998 [15] showing that early intervention with oral administration of clodronate initiated in the adjuvant setting in breast cancer patients with microscopic disease in the bone marrow, also referred to as disseminated tumor cells (DTC), at diagnosis, resulted in significant reduction of bone metastatic disease. Subsequently, several studies evaluating bisphosphonates already approved for the treatment of bone metastases, (oral clodronate, iv. pamidronate and iv. zoledronate) in a secondary prevention framework were carried out. A table summarizing these trials was presented in our recent study linking bisphosphonate (a common osteoporosis medication) treatment with improved survival in women with breast cancer [16]. Surprisingly, only two of the ten trials reported a beneficial effect on bone metastases [17,18]. The reasons for this unexpected outcome are unclear but an important variable among the groups was the proportion of postmenopausal women ranging from 0 to 61%. In this respect it is interesting to note that the Coleman study reported a beneficial survival benefit only in a subgroup of postmenopausal women [19]. Furthermore, in a recently presented meta-analysis of 41 randomized trials involving individual data on 17,751 women (10,540 who were postmenopausal), Coleman et al. [20] reported a protective effect of bisphosphonate on bone metastases for all women and an even stronger effect for postmenopausal women. There are also ongoing trials on prevention of skeletal metastases with other types of bone suppressing agents such as the more recently approved anti-RANKL monoclonal antibody for treatment of postmenopausal osteoporosis [21]. The outcome of these trials should shed further light on the ‘seed and soil’ hypothesis.

Our recently published study of a cohort of 21,664 women examined whether the use of bisphosphonates reduced the development of bone metastases in women diagnosed with breast cancer [16]. Our study was comprised predominantly of postmenopausal women with the majority (about 70%) at an early stage of the disease. As opposed to the randomized trials [20] that used bisphosphonates at high dose by iv. administration, our study examined the effect of oral bisphosphonates including alendronate (Fosamax®), risedronate (Actonel®) and etidronate (Didrocal®), all approved in Canada and in most countries for treatment or prevention of osteoporosis and given at a relatively much lower dose than those prescribed in the randomized cancer trials.

We hypothesized that the osteoporotic ‘high bone turnover terrain,’ characteristic of estrogen-deficient postmenopausal women, would support the ‘soil and seed’ mechanism of skeletal metastases development proposed by Paget. We found that use of bisphosphonates was not only associated with a very strong reduction in the risk of developing bone metastases (approximately 50%) but also a very significant and similar benefit on overall and cancer-related survival. We also examined the effect of length of exposure of the medications and found that more time on bisphosphonate results in greater reduction of bone metastases. Interestingly, women who started bisphosphonates use prior to the diagnosis of breast cancer but stopped taking the medication before or at the time of diagnosis of breast cancer had a doubling risk of developing skeletal metastases perhaps suggesting a rebound effect on bone turnover activity enhancing the potential of cancer cells to seed and grow more aggressively on this favorable terrain. Regardless of this unexpected effect, it would appear that women affected with breast cancer need sufficient length of exposure to bisphos phonates and must continue taking the medication for long periods after the diagnosis of breast cancer to achieve maximum benefit.

The mechanism(s) by which oral bisphosphonates used in this study appear to improve survival remains to be elucidated. A reduction in skeletal metastases has a direct impact on quality of life and could therefore translate into a survival benefit. Another potential mechanism lies in the purported role of bone as a ‘reservoir’ of metastatic cells that remain dormant in the bone microenvironment and later spread locally but also to extra-skeletal sites [22]. Bisphosphonates could keep these metastatic cells in a dormant state by quieting down the bone milieu in which they have settled. Finally, the known effect of bisphosphonates on inhibiting the mevalonate pathway similar to the effect of statins [3] could have an impact on cardiovascular mortality. Interestingly, we also found a beneficial effect on cardiovascular mortality in our study supporting this potential mechanism.

So what are women to do now? The conflicting reports on bisphosphonates benefits in the many prevention trials reported over the past decade created much confusion on their usefulness. The most recent trial reported using iv. zoledronate failed to achieve the desired primary outcome on survival benefit in breast cancer [20]. Consequently this drug was not approved in this context by regulatory agencies. Despite multiple lines of evidence supporting that these compounds should be very effective in preventing skeletal metastases we do not have a single clinical trial clearly demonstrating these benefits. Most, if not all, bisphosphonates on the market have now reached their patent protection lifespan and it is therefore clear that large multinational clinical trials with bisphosphonates will probably never be launched by the industry. We are therefore left with the only possible alternative of setting up such large and complex trials with the support of government agencies and/or private organizations. In the meantime we should not discourage the use of bisphosphonates in postmenopausal women suffering from osteoporosis based on recent reports of rare adverse events linked to their use such as atypical fractures of the femur [23]. One should remember that women affected by breast cancer are for the most part the ones affected by osteoporosis namely postmenopausal women. One can already observe the rippling effect of this ‘bad publicity’ on bisphosphonates use in postmenopausal women which has the potential to adversely affect the development of skeletal metastases and survival of women diagnosed with breast cancer in the population at large. This is a major public health problem that requires an urgent and coordinated action.