Toxic effects of commonly prescribed osteoporosis medications
by Dr. Robert Marx
A “drug holiday” is a temporary discontinuation in the administering of a patient’s medication. In the case of the popular class of osteoporosis drugs called bisphosphonates, it allows bone marrow to recover and new “osteoclasts” to repopulate in bone cells, where the osteoclasts had been depleted by the bisphosphonate.
Drug holidays are useful only in cases of oral bisphosphonate use uncomplicated by cancer, the cancer drug methotrexate, or the corticosteroid prednisone. This is due to low enough gastrointestinal absorption inducing only a gradual toxicity to the bone marrow, allowing the marrow to keep pace, recover in response to a drug holiday, and repopulate the lost osteoclasts. Various associations have recommended drug holidays arbitrarily, and these are not based on evidence.
Bone remodeling is the mechanism by which bone renews itself and by which it adapts to functional stress (sometimes called “Wolff’s law” or “bone modeling”). The modeling mechanism is based on osteoclasts (which break bone down) and “osteoblasts” (which secrete new bone).
The inhibition of bone remodeling by bisphosphonates results in the retention of old, hypermineralized, brittle bone, which may appear as a thickened “lamina dura” or an area of generalized sclerosis in the jaws, may die off to result in osteonecrosis of the jaw (ONJ), or may result in fractures of the femur. Bisphosphonates are irreversibly bound to bone and can be released from bone only by a process called osteoclastic acid-based resorption. Resorption is the absorption of cells (or tissue) into the circulatory system.
Osteonecrosis caused by intravenous bisphosphonates is more prevalent, more severe, less responsive to drug holidays, and less responsive to debridement surgeries than osteonecrosis induced by oral bisphosphonates. This is because intravenous bisphosphonates load and accumulate in bone at a rate 142.8 times higher than oral bisphosphonates.
The recommended doses for various oral bisphosphonates may also play a part in the severity of adverse effects. Alendronate, for example, is suggested at 70 mg per week, while residronate is suggested at 35 mg. Alendronate has accounted for more than 96% of oral bisphosphonate-induced ONJ cases and is the only oral bisphosphonate known to cause fractures of the femur.
An important lesson about osteoclasts, bisphosphonates, and drug holidays is the manner in which bone marrow recovers during the holiday. Blood serum tests reveal collagen levels (released by osteoclasts during bone resorption) which go up, as expected, upon commencement of the holiday. However, when the collagen gets to a certain high level, it falls again to an intermediate number. This seems to be the result of the drug holiday allowing bone marrow recovery and the regeneration of new osteoclasts. These new osteoclasts begin resorbing heavily bisphosphonate-loaded bone. In doing so, they die and burst (apoptosis), releasing the metabolically stable bisphosphonate into the local environment, where some of it becomes bound once again to adjacent bone. Most of it is taken up in the circulation, effectively re-dosing the body with the bisphosphonate, thereby suppressing the bone marrow osteoclasts again and lowering the serum collagen levels.
The toxic effects of bisphosphonates on bone and the resulting cases of ONJ, like studies of cases of HIV/AIDS, reinforce the age-old axiom that “disease teaches us much about normal.”