Histomorphometric and microarhitectural analyses using the 2mm bone marrow trephine in metastatic breast cancer (MBC) patients on long term bisphosphonate therapy – a feasibility study.
This research study is being done to see if the standard procedure (using a 2mm bone biopsy instrument) for collecting bone tissue is acceptable for the bone structure analysis. This study is also being done to look at the way pamidronate (Aredia®), zoledronic acid (Zometa) and clodronate (Bonefos®) change the structure of the bone after extended use. This would allow physicians to understand not only how bisphosphonates work but to understand how to better use these drugs and their potential side effects after being used for a long time.
- Feasibility of obtaining sufficient tissue using bone marrow aspirates and trephine biopsy for histomorphometry.
- Comparison between current bone mineral density and pathological analysis of bone marrow trephine biopsy looking at histomorphometry, and micro-architecture analysis.
For many years bisphosphonates have been widely used in the prevention of bone loss and osteoporosis. For oncologists the use of bisphosphonates has traditionally been in the management of patients with metastatic breast disease to the bone. In this setting bisphosphonates have been shown to delay the onset of and decrease the frequency of skeletal related events (defined as pathological bone fractures, radiotherapy/surgery to the bone, spinal cord compression, hypercalcaemia), reduce pain and improve patient quality of life. Recently increasing attention has been given to the use of bisphosphonates as anti-tumor agents in patients with early stage breast cancer and several of these studies (involving thousands of patients) will be reported in the next few years. The majority of these adjuvant bisphosphonate trials have used either oral clodronate or intravenous (IV) zoledronic acid.
When bisphosphonates are used in the oncology setting they have generally been given at potencies, doses and frequencies many times higher than when these agents are used in osteoporotic patients. For example the non-nitrogenous bisphosphonate clodronate is 10 times more potent than etidronate or the nitrogenous bisphosphonate zoledronate is 20 times more potent than alendronate. For patients with metastatic disease IV pamidronate and zoledronic acid are given every 3-4 weeks indefinitely compared with once yearly dosing of zoledronic acid in patients with osteoporosis. The effects of long term use of high dose and potency bisphosphonate upon bone homeostasis, quality, quantity, and bone architecture has not been formally investigated in the oncology setting. Understanding these effects is important as the role of bisphosphonates expands from the metastatic to the adjuvant setting as the majority of these patients will be cured of their disease and the long term toxicities of their treatment will become more important.
A group of patients who would be a good model for testing long term effects of repeat doses of highly potent bisphosphonates are those with metastatic breast cancer to the bone. These patients have a median survival of 2.5 years and will usually receive bisphosphonates for all of this time. Indeed because of different funding structures in Canada we have the opportunity to evaluate these effects with 3 commonly used bisphosphonates i.e. oral clodronate, IV pamidronate and IV zoledronic acid. In a recently completed study performed at The Ottawa Hospital Cancer Center, in which bone marrow biopsies were performed in metastatic breast cancer patients receiving bisphosphonate treatment, it was repeatedly commented on that trephines in this patient population were harder to perform than in the osteoporosis patients. In two cases the trephine needle bent instead of penetrating the bone cortex. While the bones of women with metastatic breast cancer receiving bisphosphonate therapy are clearly different, we now need to understand the nature of the quality of these bones.
In the osteoporosis literature, assessments of bone quantity are made using DEXA scanning while assessment of bone quality requires transiliac bone biopsies with a Bordier core needle (figure 1). This needle resembles the classic oncology bone marrow “Jamshidi” trephine core biopsy but differs with an internal diameter of over 7mm as well its needle length. A core of 7mm can be retrieved that includes both corticies of the iliac crest. This core can then be evaluated using traditional pathological assessment as well as histomorphometric and microarchitectural (microCT) analyses of the bone sections.
Several studies have assessed histomorphometry using a 2mm needle instead of 7mm and results were promising, suggesting that the 2mm needle technique is reliable and comparable to its 7mm counterpart1. The smaller trepine is also practical for patients with ease of procedure and less discomfort. In addition oncologists are familiar with working with the smaller Jamshidi trephine (2mm core needle).
We propose to perform a pilot study looking at the utility of this smaller needle in patients who are heavily pre-treated with bisphosphonates. If the feasibility of this technique is confirmed it provides us with a powerful tool for future studies assessing patients on repeat occasions with different therapeutic agents - something that is much more difficult when using the larger “Bordier” needle.