Introduction
Background
Osteoporosis is a systemic skeletal disorder characterized by decreased bone mass and deterioration of bony microarchitecture. The result is fragile bones and an increased risk of fractures, even after minimal trauma. Osteoporosis is a chronic condition of multifactorial etiology and is usually clinically silent until a fracture occurs. Osteoporosis is a significant health problem in the United States and around the world.
Pathophysiology
Osteoporosis results from hereditary (primary osteoporosis) and environmental factors (secondary osteoporosis) that affect both bone mass and bone quality. Traditionally, osteoporosis was described as type I (postmenopausal) or type II (senile). Postmenopausal osteoporosis (PMO) is primarily due to estrogen deficiency; senile osteoporosis is primarily due to an aging skeleton and calcium deficiency. However, it is increasingly recognized that multiple pathogenetic mechanisms interact in the development of the osteoporotic state, regardless of age.
Cortical and trabecular (cancellous) bone differ in architecture but are similar in molecular composition. Bone consists of cells and an extracellular matrix with mineralized and nonmineralized components. The composition and architecture of the extracellular matrix is what imparts mechanical properties to bone. Bone strength is determined by collagenous proteins (tensile strength) and mineralized osteoid (compressive strength).1 The greater the concentration of calcium, the greater the compressive strength.
Adult bone undergoes constant remodeling to maintain bone strength. Osteocytes, which are terminally differentiated osteoblasts embedded in mineralized bone, direct the timing and location of remodeling. Osteoblasts not only secrete and mineralize osteoid but also appear to control the bone resorption carried out by osteoclasts; thus, bone formation and resorption are coupled. Osteoclasts require weeks to resorb bone, whereas osteoblasts need months to produce new bone. Therefore, any process that increases the rate of bone remodeling results in net bone loss over time.2 Furthermore, in periods of rapid remodeling (eg, after menopause), bone is at an increased risk for fracture because the newly produced bone is less densely mineralized, the resorption sites are temporarily unfilled, and the isomerization and maturation of collagen is impaired.3
Molecular biologists have begun to elucidate the mechanisms of bone remodeling. For example, it is now understood that the receptor activator of nuclear factor-kappa B ligand (RANKL)/receptor activator of nuclear factor-kappa B (RANK)/osteoprotegerin (OPG) system is the final common pathway for bone resorption. Osteoblasts and activated T cells in the bone marrow produce the RANKL cytokine. RANKL binds to the RANK receptor expressed by osteoclasts and osteoclast precursors to promote osteoclast differentiation. Osteoprotegerin is a soluble decoy receptor that inhibits RANK-RANKL by binding and sequestering RANKL.
Bone mass peaks by the third decade of life and slowly decreases afterward. The failure to attain optimal bone strength by this point is one factor that contributes to osteoporosis. Therefore, nutrition and physical activity are important during growth and development. Nevertheless, hereditary factors play the principal role in determining an individual’s peak bone strength. In fact, genetics account for up to 80% of the variance in peak bone mass between individuals.4
Estrogen deficiency not only accelerates bone loss in postmenopausal women but also plays a role in bone loss in men. Estrogen deficiency can lead to excessive bone resorption accompanied by inadequate bone formation. Osteoblasts, osteocytes, and osteoclasts all express estrogen receptors. In addition, estrogen affects bones indirectly through cytokines and local growth factors. The estrogen-replete state may enhance osteoclast apoptosis via increased production of transforming growth factor (TGF)–beta. In the absence of estrogen, T cells promote osteoclast recruitment, differentiation, and prolonged survival via interleukin [IL]–1, IL-6, and tumor necrosis factor (TNF)–alpha. T cells also inhibit osteoblast differentiation and activity and cause premature apoptosis of osteoblasts through cytokines such as IL-7. Finally, estrogen deficiency sensitizes bone to the effects of parathyroid hormone (PTH).Calcium, vitamin D, and parathyroid hormone help maintain bone homeostasis. Insufficient dietary calcium or impaired intestinal absorption of calcium due to aging or disease can lead to secondary hyperparathyroidism. Parathyroid hormone is secreted in response to low serum calcium levels. Parathyroid hormone increases calcium resorption from bone, decreases renal calcium excretion, and increases renal production of 1,25-dihydroxyvitamin D (1,25[OH]2 D). It is this active hormonal form of vitamin D that optimizes calcium and phosphorous absorption from the gut, inhibits parathyroid hormone synthesis, and plays a minor role in bone resorption.
Vitamin D deficiency can result in secondary hyperparathyroidism via decreased intestinal calcium absorption. Interestingly, the effects of parathyroid hormone and 1,25[OH]2 D on bone are mediated via binding to osteoblasts and stimulating the RANKL/RANK pathway. Osteoclasts do not have receptors for parathyroid hormone or 1,25[OH]2 D.1
Endocrinologic conditions or medications that lead to bone loss (eg, glucocorticoids) can cause osteoporosis. Corticosteroids inhibit osteoblast function and enhance osteoblast apoptosis.5 Polymorphisms of IL-1, IL-6 and TNF-alpha, as well as their receptors, have been found to influence bone mass. Other factors implicated in the pathogenesis of osteoporosis include polymorphisms in the vitamin D receptor; alterations in insulin-like growth factor-1, bone morphogenic protein, prostaglandin E2, nitrous oxide, and leukotrienes; collagen abnormalities; and leptin-related adrenergic signaling.2
Osteoporotic fractures represent the clinical significance of these derangements in bone. Fractures occur when bones fall under excess stress. Nearly all hip fractures are related to falls.6 The frequency and direction of falls can influence the likelihood and severity of fractures. The risk of falling may be amplified by neuromuscular impairment due to vitamin D deficiency with secondary hyperparathyroidism or corticosteroids. Vertebral bodies are composed primarily of cancellous bone with interconnected horizontal and vertical trabeculae. Osteoporosis not only reduces bone mass in vertebrae but also decreases interconnectivity in their internal scaffolding.1 Therefore, minor loads can lead to vertebral compression fractures.
Frequency
United States
Approximately 10 million people in the United States have osteoporosis. An additional 33.6 million people have low bone density of the hip and are at risk for osteoporosis.7
International
Osteoporosis is estimated to affect over 200 million people worldwide.8 An estimated 75 million people in Europe, the United States, and Japan have osteoporosis.9
One in 3 women older than 50 years will eventually experience osteoporotic fractures, as will 1 in 5 men.10 By 2050, the worldwide incidence of hip fracture is projected to increase by 240% in women and 310% in men.11
Mortality/Morbidity
Osteoporosis is the most common human bone disease. In 2005, over 2 million osteoporosis-related fractures occurred in the United States.12 Hip and vertebral fractures, in particular, are associated with increased morbidity and mortality.
- Hip fractures increase the one-year risk of death by 10-20%.13,14
- Patients with hip fractures incur decreased independence and a diminished quality of life. Only one third of patients return to their prefracture level of function.15
- Among women who sustain a hip fracture, 50% spend time in a nursing home while recovering. In addition, 1 in 5 patients with hip fractures requires long-term nursing home care.7
- Persons with a hip fracture are twice as likely to experience another fracture as persons without fractures.16
- Vertebral fractures increase the 5-year risk of mortality by 15%.17
- Only one third of people with radiographic vertebral fractures are diagnosed clinically.18
- Symptoms of vertebral fracture may include back pain, height loss, and disabling kyphosis.
- Compression deformities can lead to restrictive lung disease, abdominal pain, and early satiety.
- One in 5 postmenopausal women with a new vertebral fracture incurs another vertebral fracture within one year.19
Race
Whites (especially of northern European descent) and Asian persons are at an increased risk for osteoporosis.
Sex
- Overall, osteoporosis has a female-to-male ratio of 4:1.7
- Eighty percent of hip fractures occur in women.20
Age
- The frequency of postmenopausal osteoporosis is highest in women aged 50-70 years.
- Senile osteoporosis is most common in persons aged 70 years or older.
- Secondary osteoporosis can occur in persons of any age.
- Ninety percent of hip fractures occur in persons aged 50 years or older.20
Clinical
History
Osteoporosis is typically asymptomatic until a fracture occurs. The history should focus on a thorough review of risk factors, which include the following:
- Age, sex, and race
- Family history of osteoporosis, particularly maternal history of fractures
- Reproductive factors, especially regarding early menopause and estrogen replacement therapy
- Lifestyle factors associated with decreased bone density
- Smoking
- Alcohol consumption
- Low levels of physical activity
- Strenuous exercise (such as occurs in marathon runners) that results in amenorrhea
- Calcium and vitamin D intake
- History of low-trauma “fragility" fracture in patients aged 40 years or older (A fragility fracture is defined as a fracture due to trauma that would not normally cause fracture [a force equal to or less than that resulting from a fall from standing height].)
- Signs of vertebral fracture: Vertebral fracture may be asymptomatic. Patients with vertebral fractures may note progressive kyphosis with loss of height. Some may report acute back pain after bending, lifting, or coughing.
- The pain is located in the midthoracic to lower thoracic or upper lumbar spine, where most vertebral fractures occur.
- The pain is described variably as sharp, nagging, or dull; movement may exacerbate pain. In some cases, pain radiates to the abdomen.
- Acute pain usually resolves after 4-6 weeks. In the setting of multiple fractures with severe kyphosis, the pain may become chronic.
- Coexisting medical conditions associated with bone loss (see Causes)
- Medications associated with bone loss (see Causes)
- Risk factors for falls in older patients
- Poor balance
- Orthostatic hypotension
- Weakness of the lower extremity muscles, deconditioning
- Use of medications with sedative effects
- Poor vision or hearing
- Cognitive impairment
Physical
Patients with suspected osteoporosis should undergo a comprehensive medical examination. Areas of concern include the following:
- Low body weight (body mass index <19 kg/m2)
- Signs that might indicate existing osteoporosis
- Kyphosis or dowager hump
- Point tenderness over a vertebrae or other suspected fracture site
- Signs that might indicate a secondary cause of osteoporosis (see Causes)
- Signs in older patients that may indicate increased fall risk
- Difficulty with balance or gait
- Orthostatic hypotension
- Lower-extremity weakness
- Poor vision or hearing
- Cognitive impairment
Causes
Primary causes
- Estrogen deficiency
- Changes associated with aging
Secondary causes - Up to one third of postmenopausal women, as well as many men and premenopausal women, have a coexisting cause of bone loss.21,22
Risk factors for secondary osteoporosis- Endocrine disorders -Hyperparathyroidism, hypogonadism, hyperthyroidism, diabetes mellitus, Cushing disease, prolactinoma, acromegaly, adrenal insufficiency
- Gastrointestinal/nutritional conditions -Inflammatory bowel disease, celiac disease, malnutrition, history of gastric bypass surgery, chronic liver disease, anorexia nervosa, vitamin D or calcium deficiency
- Renal disease - Chronic kidney disease, idiopathic hypercalciuria
- Rheumatologic diseases -Rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus
- Hematologic disease -Multiple myeloma, thalassemia, leukemia, lymphoma, hemophilia, sickle cell disease, systemic mastocytosis
- Genetic disorders -Cystic fibrosis, osteogenesis imperfecta, homocystinuria, Ehlers-Danlos syndrome, Marfan syndrome, hemochromatosis, hypophosphatasia
- Other - Porphyria, sarcoid, immobilization, pregnancy/lactation, chronic obstructive pulmonary disease (COPD), parenteral nutrition, HIV/AIDS
Medications known to cause or accelerate bone loss
- Corticosteroids - Prednisone (≥5 mg/d for ≥3 mo)23
- Anticonvulsants - Phenytoin, barbiturates, carbamazepine (These agents are associated with treatment-induced vitamin D deficiency.)
- Heparin (long-term)
- Chemotherapeutic/transplant drugs - Cyclosporine, tacrolimus, platinum compounds, cyclophosphamide, ifosfamide, methotrexate
- Hormonal/endocrine therapies - Gonadotropin-releasing hormone (GnRH) agonists, luteinizing hormone-releasing hormone (LHRH) analogs, depomedroxyprogesterone, excessive thyroid supplementation
- Lithium
- Aromatase inhibitors - Exemestane, anastrozole
More on Osteoporosis |
 Overview: Osteoporosis |
| Differential Diagnoses & Workup: Osteoporosis |
| Treatment & Medication: Osteoporosis |
| Follow-up: Osteoporosis |
| Multimedia: Osteoporosis |
| References |
| Further Reading |
| Next Page » |
References
Bono CM, Einhorn TA. Overview of osteoporosis: pathophysiology and determinants of bone strength. Eur Spine J. Oct 2003;12 Suppl 2:S90-6. [Medline].
Raisz LG. Pathogenesis of osteoporosis: concepts, conflicts, and prospects. J Clin Invest. Dec 2005;115(12):3318-25. [Medline].
Seeman E, Delmas PD. Bone quality--the material and structural basis of bone strength and fragility. N Engl J Med. May 25 2006;354(21):2250-61. [Medline].
Mora S, Gilsanz V. Establishment of peak bone mass. Endocrinol Metab Clin North Am. Mar 2003;32(1):39-63. [Medline].
Ringe JD, Farahmand P. Advances in the management of corticosteroid-induced osteoporosis with bisphosphonates. Clin Rheumatol. Apr 2007;26(4):474-84. [Medline].
Cummings SR, Melton LJ. Epidemiology and outcomes of osteoporotic fractures. Lancet. May 18 2002;359(9319):1761-7. [Medline].
National Osteoporosis Foundation. Clinician's Guide to Prevention and Treatment of Osteoporosis. Available at http://www.nof.org/professionals/Clinicians_Guide.htm. Accessed May 5, 2008.
Cooper C, Campion G, Melton LJ 3rd. Hip fractures in the elderly: a world-wide projection. Osteoporos Int. Nov 1992;2(6):285-9. [Medline].
Who are candidates for prevention and treatment for osteoporosis?. Osteoporos Int. 1997;7(1):1-6. [Medline].
International Osteoporosis Foundation. Facts and statistics about osteoporosis and its impact. I. Available at http://www.iofbonehealth.org/facts-and-statistics.html. Accessed May 5, 2008.
Gullberg B, Johnell O, Kanis JA. World-wide projections for hip fracture. Osteoporos Int. 1997;7(5):407-13. [Medline].
Burge R, Dawson-Hughes B, Solomon DH, et al. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005-2025. J Bone Miner Res. Mar 2007;22(3):465-75. [Medline].
Cooper C, Atkinson EJ, Jacobsen SJ, et al. Population-based study of survival after osteoporotic fractures. Am J Epidemiol. May 1 1993;137(9):1001-5. [Medline].
Vestergaard P, Rejnmark L, Mosekilde L. Increased mortality in patients with a hip fracture-effect of pre-morbid conditions and post-fracture complications. Osteoporos Int. Dec 2007;18(12):1583-93. [Medline].
Michel JP, Hoffmeyer P, Klopfenstein C, et al. Prognosis of functional recovery 1 year after hip fracture: typical patient profiles through cluster analysis. J Gerontol A Biol Sci Med Sci. Sep 2000;55(9):M508-15. [Medline].
Klotzbuecher CM, Ross PD, Landsman PB, et al. Patients with prior fractures have an increased risk of future fractures: a summary of the literature and statistical synthesis. J Bone Miner Res. Apr 2000;15(4):721-39. [Medline].
Cooper C, Atkinson EJ, Jacobsen SJ, et al. Population-based study of survival after osteoporotic fractures. Am J Epidemiol. May 1 1993;137(9):1001-5. [Medline].
Cooper C, Atkinson EJ, O'Fallon WM, et al. Incidence of clinically diagnosed vertebral fractures: a population-based study in Rochester, Minnesota, 1985-1989. J Bone Miner Res. Feb 1992;7(2):221-7. [Medline].
Lindsay R, Silverman SL, Cooper C, et al. Risk of new vertebral fracture in the year following a fracture. JAMA. Jan 17 2001;285(3):320-3. [Medline].
Smith R, Wordsworth P. Osteoporosis. In: Clinical and Biochemical Disorders of the Skeleton. 2005:123.
[Guideline] American Association of Clinical Endocrinologists medical guidelines for clinical practice for the prevention and treatment of postmenopausal osteoporosis: 2001 edition, with selected updates for 2003. Endocr Pract. Nov-Dec 2003;9(6):544-64. [Medline].
Kelman A, Lane NE. The management of secondary osteoporosis. Best Pract Res Clin Rheumatol. Dec 2005;19(6):1021-37. [Medline].
van Staa TP, Leufkens HG, Cooper C. The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis. Osteoporos Int. Oct 2002;13(10):777-87. [Medline].
The World Health Organization Fracture Risk Assessment Tool. Available at http://www.shef.ac.uk/FRAX/. Accessed May 5, 2008.
The International Society for Clinical Densitometry. 2007 ISCD Official Positions Brochure. Available at http://www.iscd.org/Visitors/positions/OfficialPositionsText.cfm. Accessed May 5, 2008.
Resnick D, Kransdorf M. Osteoporosis. In: Bone and Joint Imaging. Third Edition. 2005:551.
[Best Evidence] Bischoff-Ferrari HA, Willett WC, Wong JB, Stuck AE, Staehelin HB, Orav EJ, et al. Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a meta-analysis of randomized controlled trials. Arch Intern Med. Mar 23 2009;169(6):551-61. [Medline].
[Best Evidence] Tang BM, Eslick GD, Nowson C, Smith C, Bensoussan A. Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis. Lancet. Aug 25 2007;370(9588):657-66. [Medline].
[Guideline] Qaseem A, Snow V, Shekelle P, Hopkins R Jr, Forciea MA, Owens DK. Pharmacologic treatment of low bone density or osteoporosis to prevent fractures: a clinical practice guideline from the American College of Physicians. Ann Intern Med. Sep 16 2008;149(6):404-15. [Medline].
Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA. Jul 17 2002;288(3):321-33. [Medline].
[Best Evidence] Bouxsein ML, Chen P, Glass EV, Kallmes DF, Delmas PD, Mitlak BH. Teriparatide and raloxifene reduce the risk of new adjacent vertebral fractures in postmenopausal women with osteoporosis. Results from two randomized controlled trials. J Bone Joint Surg Am. Jun 2009;91(6):1329-38. [Medline].
Keen R. Osteoporosis: strategies for prevention and management. Best Pract Res Clin Rheumatol. Feb 2007;21(1):109-22. [Medline].
[Best Evidence] Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. May 3 2007;356(18):1809-22. [Medline].
Chaiamnuay S, Saag KG. Postmenopausal osteoporosis. What have we learned since the introduction of bisphosphonates?. Rev Endocr Metab Disord. Jun 2006;7(1-2):101-12. [Medline].
Finkelstein JS, Klibanski A, Arnold AL, et al. Prevention of estrogen deficiency-related bone loss with human parathyroid hormone-(1-34): a randomized controlled trial. JAMA. Sep 23-30 1998;280(12):1067-73. [Medline].
Holick MF. Vitamin D deficiency. N Engl J Med. Jul 19 2007;357(3):266-81. [Medline].
Kenny AM, Prestwood KM. Osteoporosis. Pathogenesis, diagnosis, and treatment in older adults. Rheum Dis Clin North Am. Aug 2000;26(3):569-91. [Medline].
Lane NE. An update on glucocorticoid-induced osteoporosis. Rheum Dis Clin North Am. Feb 2001;27(1):235-53. [Medline].
Lim PA, Brander VA, Kaelin DL, et al. Rehabilitation of orthopedic and rheumatologic disorders. 1. Osteoporosis. Arch Phys Med Rehabil. Mar 2000;81(3 Suppl 1):S55-9; quiz S78-86. [Medline].
Mulder JE, Kolatkar NS, LeBoff MS. Drug insight: Existing and emerging therapies for osteoporosis. Nat Clin Pract Endocrinol Metab. Dec 2006;2(12):670-80. [Medline].
Sambrook PN, Dequeker J, Rasp HH. Osteoporosis. In: Klipper JH, Dieppe PA, eds. Rheumatology. 2nd ed. London, UK: Mosby-Year Book; 1998:8.
Schwarz EM, Ritchlin CT. Clinical development of anti-RANKL therapy. Arthritis Res Ther. 2007;9 Suppl 1:S7. [Medline].
Strampel W, Emkey R, Civitelli R. Safety considerations with bisphosphonates for the treatment of osteoporosis. Drug Saf. 2007;30(9):755-63. [Medline].
Watts NB. Treatment of osteoporosis with bisphosphonates. Rheum Dis Clin North Am. Feb 2001;27(1):197-214. [Medline].
[Best Evidence] Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. Aug 20 2009;361(8):756-65. [Medline].
[Best Evidence] Smith MR, Egerdie B, Hernández Toriz N, Feldman R, Tammela TL, Saad F, et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med. Aug 20 2009;361(8):745-55. [Medline].
Further Reading
National Osteoporosis Foundation's Clinician's Guide to Prevention and Treatment of Osteoporosis
Additional resources on osteoporosis are available at Medscape's Osteoporosis Resource Center.
Clinical trials
Osteoporosis Among Men Treated With Androgen Deprivation for Prostate Cancer
Osteoporosis Coordinator for Low Volume Community Hospitals (ROCKET)
Strategies to Treat Osteoporosis Following a Fragility Fracture (OPTIMUS)
Addressing Vertebral Osteoporosis Incidentally Detected to Prevent Future Fractures (AVOID Fracture)
Evaluating Ways to Improve Medication Use Among People With Osteoporosis
Keywords
osteoporosis, type 1 osteoporosis, type 2 osteoporosis, postmenopausal osteoporosis, senile osteoporosis, primary osteoporosis, secondary osteoporosis, osteoporotic fracture, hip fracture, PMO, male osteoporosis, bisphosphonates, bone loss, brittle bones, dowager hump, dual-energy x-ray absorptiometry, DXA, estrogen deficiency, fragile bones, fragility fracture, hormone replacement therapy, HRT, hypogonadism, low bone mass, osteoblasts, osteoclasts, osteocytes, osteopenia, raloxifene, receptor activator nuclear factor-kappa B ligand, RANK, RANKL, secondary hyperparathyroidism, thin bones, vertebral compression fracture, vertebral fracture assessment, VFA, vitamin D deficiency
