Clogged Sewers, Stronger Bones
Science and serendipity—defined by Webster’s as finding valuable or agreeable things not sought for—often go hand-in-hand. The story of the birth of a drug class designed to strengthens bones fits.
Starting out the day by perusing the morning paper is a ritual for many. One morning in the late 1980s, a scientist in Basel, Switzerland noticed a story about calcium buildup threatening to clog up the city’s sewers. A coming catastrophe was inevitable if nothing was done to remove it. Reading on, he realized something was attracting calcium in the water moving through the system to cluster together into significant masses, inevitably blocking large pipes.
But not only was he a scientist, he worked for Novartis, a large pharmaceutical firm based in Basel. The employee in him saw a potential new profit maker that fit into the company’s business plan.
Moreover, the chemist in him realized, in terms of chemical processes at play, little-to-no difference existed between the calcium found in Basel’s underground pipes with that in human bones. Was there something in it for osteoporosis patients, potentially a huge market for the right drug?
Novartis reached out to Gregory Mundy, a gregarious Australian bone expert based at the University of Texas at San Antonio, considered by many to be among the world’s top experts in bone biology. His research found chemical agents in the calcium that had an affinity to create the buildup. One irresistibly attracted the other.
Further research by Mundy and others found the relationship of cell death and replacement – a continuous, unnoticed process taking place in all parts of the skeleton – was unbalanced in myeloma. In one, the bone’s inner process responsible for “tearing down” old bone—called osteoclasts—went into hyperdrive. The corresponding function—called osteoblasts, which produced new bone mass to replace the old, went on an indefinite vacation of sorts.
Osteoclasts were outworking the osteoblasts, explaining why myeloma patients experienced bone pain – collapsing vertebrae, cracked ribs, broken arms and legs, and other sudden, painful complications. This imbalance caused hypercalcemia, simply put, too much calcium which would collect in kidneys and, if left untreated, lead to kidney (or renal) failure.
Mundy led studies that soon applied the lessons of the chemical properties causing the calcium build up, leading to the development of a new class of drugs called bisphosphonates. And he speculated that it had the potential to transform the quality of the lives of myeloma patients.
He was correct. Over the coming decades, various types of bisphosphonates would be produced by other manufacturers to treat osteoporosis and, more significantly because of the numbers affected, breast and prostate cancers. This drug class would proliferate to make bisphosphonates among the most prescribed therapy for all cancers.
But myeloma came first. Novartis’s first drug candidate pamidronate, was proven to be effective in myeloma patients in mid-1990s clinical trials. It was approved for treatment in 1998 for myeloma, becoming commercially known as Aredia.
Although it did much to improve patients’ quality of life, it didn’t treat the myeloma cell directly, as, for example melphalan and stem cell transplants did. Instead, it treated the most common symptoms, bone weakness and hypercalcemia. Aredia replenished calcium inside bone, acting as a mortar of sorts, to strengthen it.
From today’s perspective, it is important to recall in the previous century-and-a-half that thousands of myeloma patient experiences were similar. The life span and experiences of Sarah Newbury in the early 1840s were similar to those of Brian Novis in the early 1990s. Bones breaking, lost height, an inability of the immune system to fight the weakest of biological threats.
At the first International Myeloma Foundation patient events, it was relatively easy to identify the myeloma patient in a married couple. Today one generally has to ask who the patient is. The difference between the two eras? Bisphosphonates.
Patients wished the new drug would stop myeloma from doing its dirty work, but they would use it enthusiastically. While their lives may or may not have prolonged, it unquestionably diminished or eliminated the worst side effects, which was of immeasurable value to many of them.
Aredia is an infusion drug requiring hours of administration while seated. Approved for myeloma in 2002, zoledronic acid, commercially known as Zometa, was Novartis’s second-generation bisphosphonate with an infusion time much shorter than Aredia. Except for some cases where toxicity is a concern, Zometa is preferred.
In addition to bisphosphonates, technologies including spine-stabilization surgery and treatment to inflate vertebrae with a type of balloon to put a cement-like mixture mattered. It gave immeasurable relief to patients, giving them back a day-to-day life. It didn’t restore all the lost height, but significantly relieved pain and pressure put on nerves due to bone degeneration.
There was, however, one big problem bisphosphonates could cause: osteonecrosis of the jaw. It only affected a small percentage of patients, but the misery they potentially faced was enough to wake up medical and patient communities. I provided a short background in the story of Mike Katz, a myeloma patient who first noticed some patients were suffering.
Today, physicians, nurses, and dentists work together, making sure patients have dental examinations before treatments. Even commercials for other types of bisphosphonates used more prevalently in other diseases, like Fosamax or the one with Sally Field pitching Boneva, have auctioneer-like language advising patients to get dental exams before using the drugs. Although Mike Katz and myeloma are not mentioned, they are implicit in every ad.
A new generation drug, denosumab, known commercially as XGEVA or Prolia, targets the genetic cause of osteoclast disfunction. Approved for myeloma in 2018 for patients who have had a bisphosphonate, its cost is significantly higher, leading the majority of patients to be on Zometa.
Also, the question lingers as to whether bisphosphonates have an anti-cancer effect. While there seems to be some validity to this, it’s not anything that will be game changing or significant.
In the next article, we’ll see how timing of Aredia’s unveiling mattered in the creation of a myeloma community. And of modern patient advocacy itself.
Photo: Detail, Interior, Sagrada Família, Barcelona, Spain