CASE: Bone loss and fracture in a cancer survivor
“Ms. Clark” is a 61-year-old breast cancer and thyroid cancer survivor who has osteoporosis.
As part of her breast cancer care, she completed 5 years of hormone therapy, including 3 years of tamoxifen and 2 years of an aromatase inhibitor. The care she received for thyroid cancer included suppressive therapy with thyroxine, which has yielded a thyroid-stimulating hormone (TSH) level of 0.03 mIU/L (normal range, 0.5–5.7 mIU/L).
Before starting treatment with an aromatase inhibitor, Ms. Clark’s bone density T-score at the hip was –2.6. She was given a diagnosis of osteoporosis and started on alendronate, 70 mg weekly.
Follow-up bone density study, 1 year after she completed aromatase inhibitor therapy, revealed a T-score at the hip of –2.8. Evaluation for a secondary cause of osteoporosis was unremarkable. Ms. Clark reported that she was adherent with the alendro-nate, vitamin D, and calcium regimens for osteoporosis.
Given the bone loss, a thyroid specialist recommended annual intravenous zoledronic acid (Reclast). Alternatively, her ObGyn recommended subcutaneous injection of denosumab (Prolia) every 6 months.
While Ms. Clark awaited her health insurer’s authorization of either of these two agents, she suffered a low-impact wrist fracture that necessitated reparative wrist surgery.
At this point, which one of these two alternative therapies would you recommend for Ms. Clark?
Osteoporosis manifests as low bone mass and microarchitectural disruption and fragility, with an associated increased risk of low-impact fracture. The World Health Organization defines osteoporosis as a bone mineral density (BMD) T-score ≤–2.5 (2.5 or more standard deviations below the young-adult, gender-matched reference mean).
Most authorities recommend an ounce of prevention for postmenopausal women who have osteoporosis: namely, that they be offered treatment to reduce their risk of fracture.
In Ms. Clark’s case, she was at risk of this skeletal disorder because she had been treated with an aromatase inhibitor for breast cancer and was taking a suppressive dose of thyroxine to treat thyroid cancer. In addition to exercise, calcium, and vitamin D, her initial treatment for osteoporosis was an oral bisphosphonate—an appropriate first-line agent.
Unfortunately, Ms. Clark experienced a slight decline in her BMD with this regimen. Two physicians proposed that she consider an alternative agent for the osteoporosis. One of them recommended IV zoledronic acid; the other, denosumab (TABLE).
Side by side: Denosumab and zoledronic acid for osteoporosis
| Agent | By what route is the drug given? | Are there precautions to take when administering the drug? | Have acute reactions been reported? | Does the drug increase the rate of infection? | Does it present a risk of osteonecrosis? | What is the drug’s approximate annual cost?* |
|---|---|---|---|---|---|---|
| Denosumab | Subcutaneous | No | No | Yes | Yes | $1,600 |
| Zoledronic acid | Intravenous | Yes: The medication must be infused no faster than over 15 min. The patient needs to be properly hydrated before infusion begins | Yes: Approximately 40% of patients experience an acute reaction that may include arthralgias, fever, flu-like symptoms, and myalgias | No | Yes | $1,200 |
| *To the patient, before any reimbursement by health insurance. | ||||||
Searching for secondary causes of osteoporosis
In most women who have established osteoporosis and who have not responded adequately to an oral bisphosphonate, evaluation for secondary causes of osteoporosis is warranted. The workup includes:
History identifies problems such as smoking, excessive alcohol consumption, use of a glucocorticoid, eating disorders, and bowel dysfunction that impairs vitamin D and calcium absorption, such as celiac or inflammatory bowel disease.
Physical exam focuses on assessing for low body mass index and endocrine disorders.
Laboratory evaluation includes measurement of serum chemical constituents, including calcium, phosphorus, albumin, alkaline phosphatase, and endocrine analytes, including parathyroid hormone (PTH), 25-hydroxyvitamin D, and TSH.
If a secondary cause of osteoporosis is identified, it can be treated. For example, if hyperparathyroidism is identified, removal of a parathyroid adenoma (or more than one) would likely improve bone health.
CASE CONTINUED: Evaluation comes up empty
Except for TSH, which has been suppressed as part of Ms. Clark’s thyroid cancer treatment, no abnormal findings were noted that might point to a secondary cause of osteoporosis.
CASE CONTINUED: Guided by patient preference
Ms. Clark did not want daily subcutaneous injections. If an IV medication was warranted, she preferred annual over every-3-month infusion. On her physicians’ recommendations, therefore, she focused on the pros and cons of denosumab and IV zoledronic acid.
Denosumab
Osteoclasts are the major cell type that dissolve bone mineral and resorb bone matrix. Nuclear factor kappaβ ligand (RANKL) is a circulating stimulator of osteoclast formation and, thus, osteoclast activity and bone resorption.
Denosumab, approved by the FDA in 2010 for the treatment of osteoporosis, is a human monoclonal antibody against RANKL. The drug:
- blocks the action of RANKL
- reduces osteoclast formation and activity
- reduces bone resorption.