Osteoporosis is a metabolic disease characterized by progressive thinning of the bone matrix and cortex. Fractures may result from decreased bone strength, and hip fractures are a significant cause of morbidity and mortality for aging adults. Primary osteoporosis reflects an imbalance in the coupling of osteoblasts and osteoclasts and commonly reflects natural hormonal and metabolic changes (e.g., menopause). Secondary osteoporosis makes up 5% of cases and can be caused by hyperparathyroidism, hyperthyroidism, diabetes mellitus, chronic kidney disease, hepatic disease, malabsorption syndromes, pancreatic insufficiency, malignancy, and certain medications.
Osteoporosis can occur at any age, in men as well as women, and in all racial and ethnic groups. People over age 50 are at greatest risk for osteoporosis and associated fractures. After age 50, 1 in 2 women and 1 in 6 men will have an osteoporosis-related fracture as some point. In the US, approximately 4.5 million women and 0.8 million men older than age 50 have osteoporosis, with another 23 million women and 12 million men with low bone mass (osteopenia).
In the US, whites and Asian-Americans are at greater risk than blacks or Latinos.
Blacks have greater bone densities and a lower risk of fracture, compared with white Americans. However, when fractures occur, African-American women have higher morbidity and mortality, compared with whites.
Many risk factors are associated with osteoporosis. The following are among the most common:
Age. In postmenopausal women, fracture risk increases with age. Both men and women aged 70 and older have an increased risk of fracture.
Female gender. Primary osteoporosis is 6 times more common in women than in men. Also, osteoporosis begins earlier and tends to be more severe in women.
Body habitus. Persons with lower body mass may have lower bone mineral density. Obesity reduces the risk of developing osteoporosis.
Previous fracture in the adult years.
Glucocorticoid, cyclosporine, and methotrexate treatment.
Medications. Vitamin A, heparin, aluminum-containing antacids, antidepressants, anticonvulsants, and medroxyprogesterone increase risk, whereas thiazide diuretics, estrogens, and androgens are protective.
Early onset of menopause.
Calcium or vitamin D deficiency.
Comorbid conditions, including rheumatoid arthritis, renal disease, diabetes, and inflammatory bowel disease.
Other dietary factors (see Nutritional Considerations below).
Diagnosis of osteoporosis is based on either the presence of a fragility fracture or bone mineral density that is 2.5 or more standard deviations below the average for a healthy young woman (T-score < -2.5 standard deviations) as measured by dual-energy x-ray absorptiometry. Fragility fractures most commonly occur in the vertebral body, wrist, and hip. Vertebral fracture is the most common clinical manifestation of osteoporosis or osteopenia (a diagnosis of less severe bone loss), typically presenting as an asymptomatic incidental finding on x-ray or at the time of a bone density measurement. Fracture of the vertebrae usually occurs in the lower thoracic or upper lumbar region and may occur after simple movements like bending over and lifting. Multiple fractures may result in pronounced thoracic kyphosis, sometimes called dowager’s hump. In the absence of fracture, pain is unlikely to be due to osteoporosis, but it could be due to osteomalacia or other bone disease.
Women 65 years or older and younger postmenopausal women with elevated risk should have a bone density scan. Bone biopsy, which can ensure histologic diagnosis, is rarely performed. A history of fracture is not necessary for diagnosis.
Laboratory tests, particularly thyroid-stimulating hormone, complete blood count (CBC), 25-hydroxy vitamin D, serum protein electrophoresis, urine calcium, and a comprehensive metabolic panel (including calcium and phosphate), can help determine if osteoporosis is primary or secondary. Because many disease processes can contribute to osteoporosis, disease-specific diagnostic evaluations are necessary, based on clinical presentation and screening tests.
The clinical focus should be on prevention, symptomatic therapy, and inhibition of disease progression. Consuming adequate calcium and vitamin D and getting frequent weight-bearing exercise are most important (see Nutritional Considerations).
Additional modifications include dietary changes (see Nutritional Considerations below), taking precautions to avoid falls, and smoking cessation. Smoking has an independent, dose-dependent effect on bone loss, which increases fracture risk in both sexes. Smoking increases the lifetime risk of developing a hip fracture by an estimated 31% in women and 40% in men and increases the lifetime risk for vertebral fracture by an estimated 13% in women and 32% in men. Risk declines among former smokers, but the benefit is not observed until 10 years after smoking cessation. ,
In addition to ensuring adequate calcium intake and vitamin D status at every stage of life and getting regular weight-bearing exercise, the following medications may need to be used in specific situations:
Bisphosphonates (alendronate, pamidronate, risedronate, and ibandronate) decrease bone resorption and reduce risk of vertebral and hip fractures. When they are taken orally, esophagitis and gastrointestinal side effects may occur. Avascular necrosis of the jaw is a rare but serious side effect, most commonly seen in oncology patients treated with intravenous bisphosphonates.
Anabolic agents. Teriparatide, a recombinant human parathyroid hormone and abaloparatide, a synthetic analog of human parathyroid hormone-related protein, are given as a daily subcutaneous injection for a 2-year period. They stimulate bone formation and are indicated for postmenopausal women and those at high risk for fracture who have multiple fractures or cannot tolerate other treatments. The labels carry warnings about a potential increased risk of osteosarcoma.
Denosumab, a RANKL/RANKL inhibitor, is a human monoclonal antibody given by subcutaneous injection every 6 months. It works by preventing the development and function of osteoclasts. It is indicated for the treatment of postmenopausal and male osteoporosis as well as a treatment to increase bone mass in high-risk men and women. Hypersensitivity reactions, including anaphylaxis, may occur. It can also worsen hypocalcemia, especially in patients with renal impairment.
Selective estrogen receptor modulators (SERMs, e.g., raloxifene and bazedoxifene) inhibit bone resorption. They are useful for preventing osteoporosis and reduce the risk of vertebral fractures. Like tamoxifen, raloxifene reduces breast cancer risk, but, unlike tamoxifen, it does not increase the risk of endometrial cancer. Like calcitonin, it is used to treat osteopenia. Bazedoxifene, another SERM, is also approved by the US Food and Drug Administration for use with conjugated estrogens for the osteoporosis prevention.
Estrogen use, with or without progesterone, reduces bone resorption, slows progression of osteoporosis, and reduces the risk of fragility fractures. However, the benefits of estrogens must be weighed against the many possible adverse effects of estrogen therapy, particularly the increased risk of breast cancer, myocardial infarction, and stroke.
Calcitonin decreases bone resorption, may reduce associated pain, and reduces future vertebral fractures. Although it is approved for women with osteoporosis who are at least 5 years post menopause, it is sometimes used to treat osteopenia in order to prevent further progression of bone density loss.
Testosterone may increase bone mass for men with osteoporosis (especially in males with low serum testosterone levels). If it is used, prostate-specific antigen (PSA) level should be monitored, due to the risk of progression of occult prostate cancer.
Thiazides decrease renal calcium loss and are associated with increased bone mass density, especially in those with hypercalciuria. However, they may increase the risk for electrolyte disturbances and postural hypotension.
Osteoporosis is more common where Western diets prevail. Although a common perception of this disease is that it can be prevented by a high calcium intake, evidence for such an effect is weak and conflicting. , Food and Agriculture Organization/World Health Organization data indicate calcium balance can be achieved at intakes much lower (i.e., 520 mg/d) than currently proposed, suggesting that variables other than calcium intake are critical for preventing osteoporosis-related fracture risk.
The following factors are under investigation for their role in preventing or slowing osteoporosis:
A healthful dietary pattern. A review of dietary patterns indicated that many elements of a Western diet (meats, soft drinks, fried foods, sweets, desserts, and refined grains) were inversely associated with indicators of bone health. In contrast, dietary patterns that emphasize fruits, vegetables, whole grains, nuts, and legumes were associated with greater bone mineral density and lower fracture risk. However, the hypothesis that a Western diet increases the dietary acid load and that this contributes to osteoporosis (and that an alkaline diet reduces osteoporosis risk) has not been supported by the weight of evidence.
Reduced animal protein intake. A relatively high protein intake is associated with increased bone mineral mass and reduced incidence of osteoporotic fracture. Nevertheless, the National Osteoporosis Foundation concluded that the evidence for the importance of protein in developing peak bone mass is limited. However, other evidence suggests that protein’s anabolic effect on bone is synergistic with calcium in regard to improving calcium retention and bone health in general. Quantitatively, diets that provide amounts between 0.8 g/kg of body weight up to 1.5 g/kg are considered adequate for bone health. Intakes lower than 0.8 g/kg reduce calcium absorption and increase parathyroid hormone. Supplemental protein intakes of 20-40 g/d improve bone density without affecting bone turnover markers (e.g., osteocalcin and deoxypyridinoline) and do not reduce fracture risk.
Regarding protein sources, the literature is mixed, with several studies reporting associations between high animal protein intake with greater bone mineral density and decreased risk of fracture, and others concluding that a high ratio of animal to plant protein is associated with greater fracture risk. Red meat may be the poorest choice for protein, given that the Framingham Offspring Study found that individuals obtaining most of their protein from red meat had the lowest bone mineral density. This may be due to the saturated fat content of red meat, which can reduce calcium absorption and contribute to inflammation-related bone breakdown (see below). However, meat is also high in advanced glycation end products (AGEs) which have been causally related to bone fracture. In the Cardiovascular Health Study, individuals with the highest blood levels of carboxymethyl-lysine (CML) had a 17% higher risk for hip fracture when compared with those with the lowest levels.
Consuming a greater amount of protein from soy foods may confer benefits without imparting the risks of meat intake. Like animal protein, soy increases insulin-like growth factor 1 (IGF-1), which has an anabolic effect on bone. Soy isoflavones also increase calcium absorption, osteocalcin levels, and decrease inflammatory cytokines known to activate osteoclasts. In clinical studies with postmenopausal women, soy products have been found to help prevent bone loss. ,
Increased fruit and vegetable intakes. Increased fruit and vegetable intake is associated with better bone mineral density and reduced fracture risk in both women and men. In a study of 142,000 elderly individuals, consuming 1 or fewer servings of fruits and vegetables per day was associated with a roughly 40% greater risk for hip fracture when compared with those persons who ate between 3 and 5 servings per day. Others have concluded that a reduction in hip fracture risk is mainly due to vegetable, not fruit intake. Higher intakes of potassium and bicarbonate are known to decrease calciuria and are thereby thought to be one reason for the protective effects of fruits and vegetables on bone health. However, flavonoids also appear to be responsible by affecting numerous and diverse pathways involving osteoblast differentiation and a decrease in inflammation.
Reduced sodium intake. Some studies have found that for every 2,300 mg of sodium excretion, 44 mg of calcium is lost in the urine. Habitually high sodium intakes are negatively associated with bone mineral content and bone mineral density in both pre- and post-menopausal women and with markers of bone resorption. However, the results of studies on the effects of sodium on bone metabolism are not consistent, and the hypothesis that sodium restriction can improve long-term bone integrity and fracture risk remains unproven.
Replace saturated with unsaturated fat. Saturated fat is the most important dietary determinant of serum cholesterol, and postmenopausal women with hypercholesterolemia have been found to have increased bone resorption markers and lower bone density, compared with those with normal blood lipid concentrations. In contrast, the Women’s Health Initiative and Nurses Health Studies have concluded that women consuming more omega-6 or omega-3 fats had lower fracture risk, compared with those consuming the lower amounts.
Moderation in caffeine use. Evidence regarding coffee and fracture risk is mixed and difficult to interpret, with one meta-analysis suggesting a higher risk for fractures overall and a more recent review finding no significant relationship between coffee intake and hip fracture risk. A dose-response meta-analysis found minimal risk with consumption of 2 daily cups of coffee, but a 54% higher risk in women consuming 8 cups per day, when compared to those consuming the lowest amount. Paradoxically, this study also found a protective effect of the highest level of coffee consumption for men (a roughly 25% lower risk).
Limiting alcohol intake. Alcohol decreases the endogenous production of calcitonin and may displace important bone-forming nutrients. However, a meta-analysis indicated a risk for hip fracture only at high levels (≥ 50g/d), no significant risk at moderate intakes (12.6 – 49.9 g/d) and a protective effect (12% lower risk) at intakes of 0.01 – 12.5 g/d.
Limiting supplemental vitamin A. A meta-analysis of prospective studies found a U-shaped relationship between serum retinol and risk for hip fracture. One proposed mechanism is the increased formation of osteoclasts and decreased activity of osteoblasts by retinoic acid. Vitamin A adequacy can be ensured with beta carotene from plant sources, particularly orange and yellow vegetables.
Combined supplemental vitamin D and calcium. Vitamin D alone and calcium supplementation alone are not effective for fracture prevention. However, in a recent meta-analysis, women who took both calcium and vitamin D supplements had a 30% lower risk for hip fracture and a 15% lower risk for fracture overall, compared with those not taking these supplements. Combined calcium and vitamin D supplementation has also been found effective for treating low bone mineral density caused by steroids in children with kidney diseases, persons taking antiretrovirals, and men taking anti-epileptic drugs along with risedronate.
Vitamin K. Produced by osteoblasts, osteocalcin is inactive and cannot bind calcium and other minerals until activated by vitamin K; without an adequate supply of this vitamin, calcium is more likely to be taken up by vascular smooth muscle cells and contribute to arterial stiffening and calcification. Clinical trials of phylloquinone (K1) supplementation have reported a lower risk for fracture when compared with placebo. Although green leafy vegetables are rich in vitamin K1, inadequate amounts are consumed on a Western diet, 66 and absorption from green leafy vegetables (broccoli, spinach, romaine lettuce) have been found to range from only 9%-28%. This suggests the value of consuming relatively high amounts of vitamin K-containing foods on a regular basis.
Restrict caffeine and alcohol consumption.
Female patients with osteoporosis should aim for a total calcium intake from diet and supplements of about 1500 mg/d in 3 or more divided doses, plus 800 IU/d of vitamin D. While supplemental calcium and vitamin D may benefit selected adult patients without osteoporosis, there is no theoretical basis for population-wide recommendations for high calcium intakes, particularly in males, due to associations between calcium or dairy intake and prostate cancer (see Prostate Cancer chapter).
Exercise prescription with patient-appropriate weight-bearing exercises. Physical therapy or exercise physiology consultation as needed.
Osteoporosis is a preventable and treatable disorder. Family members can help the patient maintain healthful dietary and exercise habits, and will be most supportive to the extent they follow these habits themselves.