INTRODUCTION ã…¡ Osteoporosis is a disease characterized by low bone mass and structural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. Osteoporosis itself is asymptomatic, and often remains undiagnosed until a fragility fracture occurs. An osteoporotic fracture is a fragility fracture occurring as a consequence of osteoporosis. Characteristically, fractures occur in the wrist, spine, and hip, but they can also occur in the arm, pelvis, ribs, and other bones. A fragility fracture is defined as a fracture following a fall from standing height or less, although vertebral fractures may occur spontaneously, or as a result of routine activities such as bending or lifting.
Osteoporosis is defined by the World Health Organization (WHO) as a bone mineral density (BMD) of 2.5 standard deviations below the mean peak mass (average of young healthy adults) as measured by dual-energy X-ray absorptiometry (DXA) applied to the femoral neck and reported as a T-score. However, BMD measurement does not assess the structural deterioration in bone and consequently, most osteoporotic fractures occur in women who do not have osteoporosis as defined by a T-score equal to or less than -2.5.
CAUSES AND COMPLICATIONS
Osteoporosis is the end result of an imbalance in the normal process of bone remodeling by osteoclasts and osteoblasts. During normal ageing, bone breakdown by osteoclasts increases and is not balanced by new bone formation by osteoblasts, resulting in a combination of: (1) Reduced bone mineral density (BMD), which can be measured by dual-energy X-ray absorptiometry (DXA) scanning. (2) Changes in bone composition, architecture, size, and geometry.
The age when osteoporosis becomes apparent depends on peak bone mass, which depends predominantly on genetic factors, but also levels of nutrition (particularly calcium and vitamin D), sex hormone levels (androgen and estrogen), and level of physical activity. It is reached in the third decade and starts to decline in the fifth decade for men and women. In women, this decline accelerates after the menopause for a period of between 5 and 10 years. The rate of bone loss, which depends on a number of factors including estrogen deficiency in women and decreased testosterone in older men and hyperparathyroidism. Complications of osteoporosis are fragility fractures and their consequences: (1) Hip fracture. (2) Vertebral fracture.
SCREENING
Who should be screened for osteoporosis? Recommend a DXA to check BMD and screen for osteoporosis in the following patients at high risk such as: men or women aged 50 and older with a recent low-trauma fracture, adult men or women taking chronic glucocorticoid therapy (e.g. oral prednisone ≥ 5 mg/day for three or more months or an equivalent), men aged 70 and older and women age 65 and older.
Other patients may also be good candidates for a DXA to check BMD, especially those with multiple risk factors. Assess risk factors to see if BMD testing is warranted with a thorough history in men (age 50 to 69) or postmenopausal women (under the age of 65): (1) History of delayed puberty. (2) Family history of fracture. (3) Hypogonadism. (4) Hyperparathyroidism or hyperthyroidism. (5) Chronic obstructive pulmonary disease. (6) Medications that decrease BMD (e.g. aromatase inhibitors, glucocorticoids, GnRH agonists, phenytoin, phenobarbital). (6) Excessive alcohol intake (e.g. three or more drinks per day). (7) Immobility/inactivity or repeated falls. (8) Smoking. (9) Menopausal transition. (10) Radiographic osteopenia (DXA T-score between -1 and -2.5). (11) With a fracture risk of 9.3% or greater per the Fracture Risk Assessment Tool (FRAX, available at: https://www.sheffield.ac.uk/FRAX/). Risk assessment can also be done using a risk assessment tool (e.g. FRAX). FRAX is not intended to be used for premenopausal women, patients on or recently on (within the last two years) osteoporosis treatment.
MANAGEMENT
Who should be offered treatment for osteoporosis? Postmenopausal women, and men age 50 and older, with a T-score of -2.5 or lower (i.e. osteoporosis). Postmenopausal women, and men age 50 and older, with a previous hip or spine fracture. Also, patients with a T-score between -1 and -2.5 (i.e. osteopenia) with the following risks per the FRAX tool: (1) 10-year hip fracture risk of 3% or higher. (2) 10-year risk of major osteoporotic fracture of 20% or higher. Consider treatment for patients with low-trauma or fragility fracture
When should screening be done during osteoporosis treatment? Some experts believe it is not necessary to check a DXA in patients currently receiving osteoporosis treatment. Women receiving osteoporosis treatment may have reduced fractures regardless of impact on BMD. There is no evidence to support monitoring BMD in men receiving osteoporosis treatment. Others recommend continuing to check a DXA during treatment until BMD has stabilized or after three to five years of bisphosphonate therapy. Check a DXA every two to five years after osteoporosis medications are stopped (three to five years after bisphosphonates [Canadian guidelines]). Some experts may base the time to check a DXA on the previous therapy used. For example, among some of the bisphosphonates, holidays may be able to be longer for zoledronic acid or shorter for risedronate, due to their binding affinity for bone and potential for residual effects. Indications for checking DXA more frequently may include a new fracture or starting a long-term corticosteroid (i.e. > 2.5 mg/day for three or more months).
Consider restarting an osteoporosis medication if: (1) Significant declines in BMD (e.g. DXA T-score drops to -2.5 or below [i.e. osteoporosis]). (2) New risk factors develop (e.g. a new fracture, starting long-term corticosteroid). (3) Bone resorption markers rise (e.g. C-terminal telopeptide type-1 collagen [CTX] or N-terminal telopeptide type-1 collagen).
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Note: This may not be appropriate for patients who had low bone resorption markers prior to treatment.
PHARMACOLOGICAL THERAPY
Oral
Bisphosphonates (Alendronate [Fosamax], Etidronate/calcium
carbonate - etidronate is NOT approved for osteoporosis in the U.S.
Intravenous (IV) Bisphosphonates (Zoledronic acid [Aclasta] and Ibandronate [Boniva]). Consider for prevention and treatment in: (1) Patient unable to take oral bisphosphonates due to gastrointestinal issues. (2) Patient unwilling to follow oral bisphosphonate dosing instructions. (3) When adherence is a concern with oral bisphosphonates. (3) Patient with corticosteroid-induced osteoporosis who is not appropriate for oral bisphosphonates. Avoid in patients with hypocalcemia and renal insufficiency (e.g. CrCl < 30 mL/min).
Conjugated estrogen/bazedoxifene (SERM). Consider for prevention of postmenopausal osteoporosis in women < 75 years old with a uterus, especially if they require treatment for vasomotor menopausal symptoms. Avoid in patients, (1) With known or history of breast cancer or thromboembolism. (2) With hepatic or renal impairment. (3) With a deficiency of protein C, S, or antithrombin.
Do not take with a progestin, additional estrogen, or an additional SERM.
Doses may be held during admissions due to increased risk of thromboembolism associated with immobility.
Selective estrogen receptor modifier (SERM) ― Raloxifene (Evista). Consider for prevention and treatment in: (1) Postmenopausal women at high risk of breast cancer (especially when hip fracture risk is not significant) or who cannot use a bisphosphonate or denosumab. (2) Younger women (e.g. < 60 years old) at greater risk of vertebral than hip fractures. (3) Postmenopausal women with corticosteroid-induced osteoporosis unable to take oral/IV bisphosphonates, parathyroid hormone analogs, or denosumab. Avoid in patients, (1) With hot flashes. (2) With history of venous thromboembolism. (3) In whom hip fracture is the primary concern.
Calcitonin nasal spray (U.S. only). Consider for treatment in postmenopausal women who cannot use a bisphosphonate, raloxifene, estrogen, denosumab, abaloparatide, or teriparatide. and who with bone pain from vertebral compression fractures. Avoid in patients, (1) In whom hip fracture is the primary concern. (2) Less than 5 years postmenopausal (not proven effective).
Parathyroid Hormone Analogs (Abaloparatide [Tymlos] and Teriparatide [Forteo]). Consider for treatment in postmenopausal women with high fracture risk (e.g., corticosteroid-induced osteoporosis, previous osteoporotic fracture, multiple risk factors, very low BMD) and those who failed or cannot use other agents. Teriparatide may be considered for: (1) Primary or hypogonadal osteoporosis (men). (2) Corticosteroid-induced osteoporosis after considering oral/IV bisphosphonates. Avoid in patients, (1) Abaloparatide: with pre-existing hypercalcemia or an underlying hypercalcemic disorder, (e.g., primary hyperparathyroidism). (2) Teriparatide: with metabolic bone disease, Paget’s disease, previous skeletal irradiation and with elevated alkaline phosphatase of unknown etiology.
Receptor activator of nuclear factor kappa-B ligand (RANKL inhibitor) ― Denosumab (Prolia). Consider for treatment in patients with high fracture risk (e.g. previous fracture, multiple risk factors): (1) Men and postmenopausal women with osteoporosis, especially those who have failed or can’t/won’t take bisphosphonates, such as patients who have renal insufficiency. (2) With prostate cancer, receiving androgen deprivation therapy for prostate cancer. (3) With breast cancer, receiving an aromatase inhibitor. (3) With or at risk for corticosteroid-induced osteoporosis and unable to take oral or IV bisphosphonate or parathyroid hormone analogs. Avoid in patients, (1) With significant renal insufficiency due to high risk of hypocalcemia (unless carefully monitoring) or in patients on dialysis due to limited data in this patient population. (2) With hypocalcemia.
Sclerostin Inhibitor (Romosozumab). Consider for treatment in postmenopausal women with high fracture risk (e.g. previous osteoporotic fracture, multiple risk factors). Also consider for treatment in postmenopausal women who failed or cannot use other agents (U.S. only). Limited data suggest safe and effective use in men with a previous fracture who failed or cannot use other agents. Avoid in patients, (1) With CV risk factors, especially those who have had a myocardial infarction or stroke (per U.S. labeling, in the last 12 months). CV adverse events have not been consistently seen in all studies. However, in one study, one year of romosozumab was associated with an increase in cardiac ischemic events (NNH = 200) compared to alendronate. Numbers needed to treat (NNT) are in comparison to placebo, unless otherwise noted. The FDA is requiring post-marketing data to further evaluate the CV safety of romosozumab. (2) With hypocalcemia (correct prior to starting therapy).
REFERENCES
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