ABIM Exam Disease of the Week Profile: Osteoporosis
Osteoporosis is a disease in which bone strength is compromised, which leads to increased risk of fractures. The main mechanism involved in osteoporosis is an imbalance between osteoblastic activity and osteoclastic activity. Osteoblast cells play a role in bone formation; whereas, osteoclast cells are involved in bone resorption. When the balance shifts in the direction of bone resorption, individuals are at increased risk of developing osteoporosis.
In normal bone, approximately ten percent of the bone structure is always undergoing remodeling in the matrix. The three main mechanisms of osteoporosis development are: inadequate peak bone mass, excessive bone resorption, and lack of new bone formation during remodeling. The interplay of these three mechanisms makes bones more prone to fracture.
Understanding molecular signal pathways helps elucidate how osteoporosis can develop. Osteoblasts produce a molecule called Receptor Activator for Nuclear Factor Kappa B ligand (or RANKL for short). RANKL binds to receptors on osteoclast cells to activate these cells, leading to bone resorption. Osteoprotegerin (OPG) binds to RANKL to prevent it from binding to RANK receptors and, therefore, inhibits osteoclast cell activation. OPG is also known as osteoclastogenesis inhibitory factor (or OCIF for short). Another known molecular pathway that is well understood is the WNT1 signaling pathway. WNT1 induces osteoblast differentiation and bone formation in the early osteoblast progenitor cells. When there is a mutation in the WNT1 signaling pathway, it impairs bone formation and can lead to early osteoporosis.
Some of the most common risk factors for the development of osteoporosis can be divided into medical conditions, medications, and other causes.
Medical conditions associated with osteoporosis are primary hyperparathyroidism, uncontrolled primary hyperthyroidism, multiple myeloma, hypogonadism (males with low testosterone level), and vitamin D deficiency. Vitamin D deficiency can result from lack of sunlight or malabsorption syndromes like celiac disease.
Common medications that can cause osteoporosis to are long term steroid use, phenytoin (used for seizures), long term heparin (anticoagulant), LHRH aganoists like lupride (used for prostate cancer), and aromatase inhibitors like anastrozole. Anastrozole is used in post-menopausal women who are ER/PR positive breast cancer patients.
Other risk factors include advanced age, sedentary lifestyle (biggest risk factor), post-menopausal women, low body mass index, and increased alcohol consumption.
Osteoporosis usually does not have any presenting symptoms except that it should be suspected in individuals who have these above risk factors and develop bone fractures.
Diagnosis of osteoporosis is obtained by measuring bone mineral density on dual-energy x-ray absorption (DEXA) scan. DEXA scan results are typically reported as T scores. Osteoporosis is diagnosed when there is a history of at least one or more fragility fracture in conjunction with a T-score of less than -2.5.
Treatment of osteoporosis initially involves calcium and vitamin D supplements. It is recommended for patients to have 1200-1500mg calcium per day and 800-1000 IU vitamin D per day. However, if patients have severe vitamin D deficiency (as indicated by a 25-hydroxyvitamin D level less than 10 nmol/L), then vitamin D 50,000 IU/week for about 2 months can be given. Along with calcium and vitamin D, bisphosphonates are the mainstay of treatment for osteoporosis.
The most well recognized bisphosphonates are alendronate and risedronate, which reduce the risk of vertebral and non-vertebral fractures. These medications are usually the first line treatment in post-menopausal women. Intravenous zoledronate is another option but is more often used in osteoporosis in individuals who have malignancy related hypercalcemia or cannot tolerate oral bisphosphonates.
Teriparatide (recombinant human parathyroid hormone) is reserved for treating patients at high risk of fracture, which includes those patients with a T score of less than -3.0 or less and if there is a contraindication to bisphosphonate therapy.
Males who develop osteoporosis because of hypogonadism can benefit from testosterone replacement therapy. Along with these treatment options for osteoporosis, weight resistance training proves to be effective in strengthening bones. Smoking cessation is essential for those who use nicotine.
Bisphosphonates should be taken standing upright with a full glass of water and on an empty stomach. Otherwise, bisphosphonate use can place the patient at risk of pill-induced esophagitis. Another side effect—albeit a rare one—of bisphosphonate therapy is osteonecrosis of the jaw.
It is recommended that bisphosphonates can be taken for up to five years. After five years of treatment, if a DEXA scan shows improvement or stabilization of the T score, patients can undergo a “bisphosphonate holiday” for about three years. At that time, another DEXA scan should be performed. If the T score has worsened or if the patient has developed new fractures, then bisphosphonate therapy should be resumed. Calcium supplements, vitamin D, and weight resistance training, however, should not be discontinued.
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