Osteoporosis, meaning porous bone, is a metabolic disease characterized by progressive thinning and disrupted architecture of bone. 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, autoimmune conditions, neurological conditions, and certain medications.

While it can occur at any age and in all racial and ethnic groups, people over age 50 are at greatest risk for osteoporosis and associated fractures. In the United States, approximately 8 million women and 2 million men older than age 50 have osteoporosis. Another 27 million women and 16 million men have low bone mass (osteopenia).[1] After age 50, 1 in 2 women and 1 in 4 men will have an osteoporosis-related fracture as some point. Fractures can be minor or life-altering, with hip fractures causing significant morbidity and mortality for aging adults.

Risk Factors

In the US, non-Hispanic White and Asian American individuals are at greater risk than Black or Latino individuals.

Black Americans have greater bone densities and a lower risk of fracture, compared with White Americans.[2] When fractures occur, however, Black women have higher morbidity and mortality compared with White women.[3]

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 sex. Primary osteoporosis is 6 times more common in women than in men. Also, osteoporosis begins earlier and tends to be more severe in women. After age 65, the incidence of osteoporosis in women is 5 times that in men.

Body habitus. Persons with lower body mass may have lower bone mineral density. Higher body mass reduces the risk of developing osteoporosis.

Sedentary lifestyle.

Genetic factors.

Previous fracture in the adult years.

Smoking.

Glucocorticoid, cyclosporine, and methotrexate treatment.

Medications. Vitamin A, heparin, aluminum-containing antacids, selective serotonin reuptake inhibitor antidepressants, anticonvulsants, proton pump inhibitors, and medroxyprogesterone, among others, increase risk, whereas thiazide diuretics, estrogens, and androgens are protective.

High alcohol consumption. High alcohol intake is associated with greater fracture risk. However, a moderate to low alcohol intake is associated with reduced risk.[4][5]

Nulliparity.

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

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 (DEXA).[6] For males, some professional societies use young male references ranges, although the World Health Organization recommends using female reference ranges for men.

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, with a T-score of -1 to -2.5 standard deviations), typically presenting as an asymptomatic incidental finding on an 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.[7] 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. Additionally, some professional societies recommend men be screened at age 70 or between 50-69 if additional clinical risk factors are present. Bone biopsy, which can ensure histologic diagnosis, is rarely performed. A history of fracture is not necessary for diagnosis.

In women with low bone mineral density, an initial laboratory evaluation should include complete blood count, 25-hydroxy vitamin D, and a comprehensive metabolic panel (including serum creatinine, liver enzymes, alkaline phosphatase, calcium, and phosphate). Because many disease processes can contribute to osteoporosis, disease-specific diagnostic evaluations are necessary and should be based on clinical presentation and screening tests. Other measures that may be considered based on patient presentation and initial screening include thyroid function panel, parathyroid hormone, serum and urine protein electrophoresis, and urine studies (urine calcium, phosphorus, cortisol).

Treatment

The clinical focus should be on prevention, symptomatic therapy, and inhibition of disease progression. Consuming adequate calcium and vitamin D and participating in frequent weight-bearing and resistance exercises are most important.[5] This kind of physical activity is helpful for increasing the bone mineral density of the spine in postmenopausal women and for preventing and treating osteoporosis.[8][9]

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.[10][11]

Medications

The following medications may be used in specific situations:

Bisphosphonates (alendronate, pamidronate, risedronate, and ibandronate) decrease bone resorption and reduce risk of vertebral and hip fractures. When bisphosphonates 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 analogue 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, those who have multiple fractures, or those who 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 activity 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 osteoporosis prevention.[12]

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, but as it is associated with a poor overall effect on bone density in comparison with bisphosphonates, its use in osteoporosis treatment is not highly recommended.

Testosterone may increase bone mass for men with osteoporosis, especially in males with low serum testosterone levels, but this may be due to its conversion to estrogen by aromatase. It is not recommended for osteoporosis treatment in men or women.

Thiazide diuretics decrease renal calcium loss, which may potentially affect bone mineral density. These drugs could be a considered first-line treatment option for individuals with hypertension and concomitant osteopenia or osteoporosis. However, they are not considered part of any osteoporosis treatment protocol.

Nutritional Considerations

Osteoporosis is more common where Western diets prevail.[13] 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.[14][15] Food and Agriculture Organization/World Health Organization data indicate calcium balance can be achieved at intakes much lower (i.e., 520 mg/day) than currently proposed, suggesting that variables other than calcium intake are critical for preventing osteoporosis-related fracture risk.[16]

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.[17] However, the hypothesis that increased dietary acid load contributes to osteoporosis risk has not been adequately supported by evidence.[16]

Reduced animal protein intake. A relatively high protein intake is associated with increased bone mineral mass and reduced incidence of osteoporotic fracture.[18] Nevertheless, the National Osteoporosis Foundation concluded that the evidence for the importance of protein in developing peak bone mass is limited.[19] 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.[20] 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.[21] Supplemental protein intakes of 20-40 g/day improve bone density without affecting bone turnover markers (e.g., osteocalcin and deoxypyridinoline) and do not reduce fracture risk.[22]

Research findings have been mixed regarding protein sources, 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.[23] 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, which have been causally related to bone fracture.[24][25] In the Cardiovascular Health Study, individuals with the highest blood levels of carboxymethyl-lysine, a glycation end product, had a 17% higher risk for hip fracture when compared with those with the lowest levels.[26]

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 and osteocalcin levels and decrease inflammatory cytokines known to activate osteoclasts.[16] In clinical studies with postmenopausal women, soy products have been found to help prevent bone loss.[27][28]

Increased fruit and vegetable intake. 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.[29] Other studies have concluded that a reduction in hip fracture risk is mainly due to vegetable, not fruit, intake.[30] 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. Flavonoids also appear to be responsible by affecting numerous and diverse pathways involving osteoblast differentiation and decreased inflammation.[31]

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.[32] Habitually high sodium intakes are negatively associated with bone mineral content and bone mineral density in both pre- and postmenopausal women. The results of studies on the effects of sodium on bone metabolism are not consistent, however, and the hypothesis that sodium restriction can improve long-term bone integrity and fracture risk remains unproven.[33]

Minimizing saturated fat intake. Saturated fat intake is the most important dietary determinant of plasma cholesterol. 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.[34] In contrast, the Women’s Health Initiative study and Nurses Health Study have concluded that women consuming more omega-6 or omega-3 fats had lower fracture risk compared with those consuming less.[35]

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.[36][37] 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 with 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).[38]

Limiting alcohol intake. Alcohol decreases the endogenous production of calcitonin and may displace important bone-forming nutrients.[39] However, a meta-analysis indicated a risk for hip fracture only at high levels (≥ 50 g/day), no significant risk at moderate intakes (12.6-49.9 g/day), and a protective effect (12% lower risk) at intakes of 0.01-12.5 g/day.[40]

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.[34] 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.[41][42] In a recent meta-analysis, however, 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.[43] 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 antiepileptic drugs along with risedronate.[44][45][46]

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.[47] Clinical trials of phylloquinone (K1) supplementation have reported a lower risk for fracture when compared with placebo.[48] Although green leafy vegetables are rich in vitamin K1, inadequate amounts are consumed on a Western diet, and absorption from green leafy vegetables (broccoli, spinach, romaine lettuce) has been found to range from only 9-28%.[49] This suggests the value of consuming relatively high amounts of vitamin K-containing foods on a regular basis.

Orders

See Basic Diet Orders chapter.

Low-sodium diet.

Restrict caffeine and alcohol consumption.

Female patients with osteoporosis should aim for a total calcium intake from diet and supplements of about 1,200 mg/day in 3 or more divided doses, plus 800 IU/day of vitamin D. While supplemental calcium and vitamin D may benefit some adult patients without osteoporosis, there is no theoretical basis for population-wide recommendations for high calcium intakes. This is particularly true for males because of associations between calcium or dairy intake and prostate cancer (see Prostate Cancer chapter).

Smoking cessation.

Exercise prescription with patient-appropriate weight-bearing exercises. Physical therapy or exercise physiology consultation as needed.

What to Tell the Family

Osteoporosis is a largely preventable and treatable disorder of bone mineral density. 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.

References