Guidelines by the National Osteoporosis Foundation (NOF) recommend osteoporosis treatment in postmenopausal women or men age 50 years and older with a T-score of less than −2.5 at the femoral neck, hip, or spine; patients with low bone mass (T-score between −1.0 and −2.5) and a 10-year probability of hip fracture of ≥3% or a 10-year probability of major osteoporosis-related fracture of ≥20%, as determined by FRAX; and in patients with a fragility fracture.
Current osteoporosis therapy are divided into antiresorptive and anabolic agents (Table 27–5). Antiresorptive therapy available in the United States are bisphosphonates, hormone replacement therapy (HRT), selective estrogen receptor modulators (SERMs), denosumab, and calcitonin. Parathyroid hormone is the only anabolic agent available in the United States.
Table 27–5.FDA approved agents for osteoporosis. ||Download (.pdf) Table 27–5. FDA approved agents for osteoporosis.
|Agent ||Efficacy ||Side Effects ||Dosing ||Delivery |
|Bisphosphonates: || || || || |
| ||Reduced vertebral, hip, and nonvertebral fractures (no data on ibandronate for hip fracture) || ||5–10 mg oral daily, 70 mg oral weekly 5 mg oral daily, 35 mg oral weekly, 150 mg oral monthly 2.5 mg oral daily, 150 mg oral monthly, 3 mg IV every 3 months 5 mg IV every 12 months |
|Hormone Replacement Therapy ||Reduced vertebral, hip, and nonvertebral fractures || ||Multiple oral and transdermal formulations |
|Raloxifene (selective estrogen receptor modulator) ||Reduced vertebral fractures || ||60 mg oral daily |
|Calcitonin ||Reduced vertebral fractures || ||200 IU 100 IU ||Nasal spray daily (alternate each side of nostril) Subcutaneous or intramuscular every other day |
|Denosumab ||Reduced vertebral, hip and nonvertebral fractures || ||60 mg ||Subcutaneously every 6 months |
|Teriparatide ||Reduced vertebral, hip and nonvertebral fractures || ||20 mcg ||Daily subcutaneous injections for 24 months |
Bisphosphonates are potent antiresorptive agents that bind hydroxyapatite crystals on bone surfaces and permanently inhibit osteoclast function. FDA-approved agents are alendronate, risedronate, ibandronate and zoledronic acid.
Bisphosphonates may be given orally on a daily (alendronate, risedronate), weekly (alendronate, risedronate), or monthly (risedronate, ibandronate) schedule or intravenously every 3 months (ibandronate) or intravenously once yearly (zoledronic acid). Oral bisphosphonates must be taken on an empty stomach because of their poor absorption and bioavailability. Patients must sit upright and fast for 30 minutes (with alendronate and risedronate) to 60 minutes (with ibandronate) after ingestion. Prior to the initiation of any bisphosphonates therapy, calcium and vitamin D must be adequately repleted because of the possibility of inducing hypocalcemia, especially in older adults.
Oral bisphosphonates are commonly associated with gastrointestinal side effects, including dyspepsia, heartburn, indigestion, and pain while swallowing. More serious gastrointestinal effects include erosive esophagitis and esophageal ulcerations; thus patients are reminded to take a full glass of water (6–8 oz) and remain upright after the dose. Acute phase reactions (fever, myalgia, arthralgia, headache, and flu-like symptoms) have been reported with both oral and intravenous bisphosphonates. Intravenous zoledronic acid has been associated with acute renal failure and should be used with caution in patients with renal impairment. Alendronate should also be used with caution in patients with severe renal insufficiency (creatinine clearance <35 mL/min). Long-term effects, including osteonecrosis of the jaw and atypical fracture, are rare and benefits from fracture reduction outweigh the harms.
All bisphosphonates have been shown to significantly improve BMD of the spine and reduce risk of vertebral and hip fractures. There are no published data for hip fracture reductions with ibandronate in randomized clinical trials. There are no studies of comparative efficacy of the bisphosphonates with each other.
The duration of bisphosphonate therapy is not yet clear. Seven-year follow-up of patients using alendronate showed that spinal BMD continued to increase through 7 years of treatment and remained stable. After the withdrawal of treatment, there was a small increase in biochemical markers of bone turnover. It appears that skeletal benefits may be preserved for at least 1–2 years after cessation, but long-term follow-up studies are needed.
Hormone Replacement Therapy
Hormone replacement therapy (HRT) is approved for the prevention of osteoporosis in postmenopausal women, although the primary indication is for the treatment of moderate-to-severe menopausal symptoms. The exact mechanism of HRT on bone remodeling has not been elucidated, however it is clear that the loss of estrogen during menopause results in an acceleration of bone resorption in most women.
Combined estrogen and progesterone therapy have produced a 1.4% to 3.9% increase in BMD at skeletal sites. Studies have shown that estrogen reduces the risk for vertebral and hip fracture, as well as the risk of nonvertebral fracture. In the WHI trial, treatment of postmenopausal women with combined therapy reduced the risk of hip fracture by 33%.
The timing of initiation and duration of HRT remains unclear. It is suggested that women start estrogen within 2–7 years of menopause. Several studies have shown that HRT begun before 60 years of age prevents nonvertebral, hip, and wrist fractures, but there is insufficient evidence that fracture risk is reduced when HRT is begun after age 60 years. Estrogen begun and continued after age 60 years appears to maintain BMD. The duration of therapy necessary to protect women against fragility fractures is indefinite. HRT can be administered as an oral or transdermal formulation. It may be given on a continuous basis, with no interruption in therapy, or as a cyclical regimen.
Compliance with HRT is typically poor because of common side effects and concern about increased incidence of breast or endometrial cancer. Women who have not undergone hysterectomy should have progestin added to the estrogen regimen to prevent endometrial hyperplasia. Low-dose HRT can reduce the amount of uterine bleeding, fluid retention, mastalgia, and headaches, making estrogen therapy much easier to tolerate.
Safety results from the WHI study showed an increased risk of coronary heart disease, pulmonary embolism, and stroke associated with the use of combined hormonal therapy in women with an intact uterus. As a result, HRT is considered second line therapy for only prevention of osteoporosis in young perimenopausal women with menopausal symptoms.
Selective Estrogen Receptor Modulators
SERMs are compounds that bind to and activate estrogen receptors but have agonist/antagonist properties at different tissue sites. Raloxifene is approved for the prevention and treatment of postmenopausal osteoporosis and indicated for the reduction of invasive breast cancer.
Raloxifene at 60 mg per day has been shown to increase BMD by 2% and reduce the risk of new vertebral fracture by 40% after 2 years. However, raloxifene has not demonstrated a protective effect on nonvertebral or hip fracture risk.
Calcitonin, an endogenous hormone secreted by the parafollicular C cells of the thyroid gland, which helps to maintain calcium homeostasis. Calcitonin acts directly on osteoclasts, with inhibitory effects on bone resorption. Calcitonin is approved for the treatment of postmenopausal osteoporosis. Calcitonin nasal spray has been shown to have modest effects on spine BMD (1.5% increase) and significantly reduce the risk of new vertebral fractures by 33% in women with prevalent vertebral fractures. There was no significant effect on hip or nonvertebral fracture risk. Calcitonin is an option for women who cannot tolerate bisphosphonates or SERMs. In some patients, calcitonin has an analgesic effect, making it suitable for patients with acute vertebral fracture. Calcitonin nasal spray is generally administered once per day, alternating nostrils daily. Injectable calcitonin can be administered subcutaneously or intramuscularly.
Denosumab is a human monoclonal antibody with a high affinity and specificity for RANKL. When denosumab binds to RANKL, it prevents RANKL–RANK interaction resulting in a decrease in osteoclastic bone resorption.
Denosumab is approved for osteoporosis treatment. Results from phase 3 study in women with osteoporosis showed that treatment with denosumab increased lumbar spine BMD by 6.5%, and significantly reduced the risk of vertebral (68%) and hip (40%) fractures compared with placebo. Prior to starting denosumab, patients with preexisting hypocalcemia must have this condition corrected because it could worsen with treatment. Denosumab may be given to patients with renal impairment without dose adjustment.
Teriparatide is an FDA-approved anabolic agent that is synthetic PTH. It stimulates bone remodeling, preferentially increasing formation over resorption, and reduces the risk of new vertebral fractures (65% reduction) and nonvertebral fractures (35%) with significant improvements in BMD of 10% to 14%.
Teriparatide is administered as daily subcutaneous injections. Eleven percent of patients developed mild hypercalcemia. Osteosarcomas have been induced in rats given teriparatide. However, an independent oncology advisory board concluded that the rat carcinogenicity data are very unlikely to have clinical relevance in humans being treated with teriparatide for a relatively short duration (it is approved for only 2 years’ use).
Upon termination of teriparatide treatment, sequential therapy with an oral or IV bisphosphonate may strengthen the beneficial effects of teriparatide. Concurrent therapy with teriparatide and oral bisphosphonates has been avoided because oral bisphosphonates have been shown to reduce the positive effects of teriparatide on bone turnover.
In summary, given a choice of pharmacotherapy, clinical risk factors for fracture and comorbidities should be taken into account when tailoring therapy for osteoporosis. Risk factors such as age and previous fracture are critical to choosing an optimal treatment strategy. Clinicians need to be aware of the safety concerns associated with each drug and treatment should be made on an individual basis taking into account the relative benefits and risks in different patient population.
et al Exercise for preventing and treating osteoporosis in postmenopausal women. Cochrane Database Syst Rev. 2002;(3):CD000333.
A. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005-2025. J Bone Miner Res
Consensus development conference: diagnosis, prophylaxis and treatment of osteoporosis. Am J Med
JT. Clinical practice. Vertebral fractures. N Engl J Med
et al Interventions for preventing falls in older people living in the community. Cochrane Database Syst Rev. 2009;(2):CD007146.
MJ. Hip protectors for preventing hip fractures in older people. Cochrane Database Syst Rev. 2010;(10):CD001255.
A. Integreated imaging approach to osteoporosis: state of the art review and update. Radiographics
D. Bone health across the generations: a primer for health providers concerned with osteoporosis prevention. Maturitas
C. Osteoporosis: impact on health and economics. Nat Rev Rheumatol
EV. The effects of a FRAX revision for the USA. Osteoporosis Int
F. Development and use of FRAX in osteoporosis. Osteoporosis Int. 2010;21 Suppl 2:S407-–S413.
E. FRAX and its applications to clinical practice. Bone
. 2009; 44(5):734-–743.CrossRef
G, van Kuijk
JE. Radiologic assessment of osteoporotic vertebral fractures: diagnostic and prognostic implications. Eur Radiol
et al Screening for osteoporosis in men: a systematic review for an American College of Physicians guideline. Ann Intern Med
H. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ
BL. Vertebral fractures predict subsequent fractures. Osteoporosis Int
. 1999;10(3):214-–221. National Osteoporosis Foundation. NOF releases updated data and national breakdown of adults age 50 and older affected by osteoporosis and low bone mass. Washington, DC. NOF Press Release, Nov 1, 2013. Available from: http://nof.org/news/1648
S ed. Bone Health and Osteoporosis: A Report of the Surgeon-General. Rockville, MD: US Department of Health and Human Services; 2004.
MC. Osteoporosis in men: update 2011. Rheum Dis Clin North Am
et al Collaborative meta-analysis: associations of 150 candidate genes with osteoporosis and osteoporotic fracture. Ann Intern Med
M. The role of physical activity in the prevention of osteoporosis in postmenopausal women. An update. Maturitas
et al Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res
C. Individualizing osteoporosis therapy. Osteoporosis Int
A. Primary care use of FRAX: absolute fracture risk assessment in postmenopausal women and older men. Postgrad Med
et al Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards. Osteoporos Int
HD. Calcium intake and risk of cardiovascular disease: a review of prospective studies and randomized clinical trials. Am J Cardiovasc Drugs
E. Minor, major, low-trauma, and high-trauma fractures: what are the subsequent fracture risks and how do they vary? Curr Osteoporos Rep
NC. Early life factors in pathogenesis of osteoporosis. Curr Osteoporos Rep
World Health Organization. Techinical Report: Assessment of Fracture Risk and Its Application to Screening for Postmenopausal Osteoporsis: A Report of a WHO Study Group. Geneva, Switzerland: World Health Organiation; 1994.