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). 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.
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. When fractures occur, however, Black women have higher morbidity and mortality compared with White women.
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.
Previous fracture in the adult years.
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.
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 (DEXA). 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. 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).
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. 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.
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.
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.
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.
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/day) 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 increased dietary acid load contributes to osteoporosis risk has not been adequately supported by 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/day improve bone density without affecting bone turnover markers (e.g., osteocalcin and deoxypyridinoline) and do not reduce fracture risk.
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. 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. 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.
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. In clinical studies with postmenopausal women, soy products have been found to help prevent bone loss.
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. Other studies 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. Flavonoids also appear to be responsible by affecting numerous and diverse pathways involving osteoblast differentiation and decreased 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 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.
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. 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.
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 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).
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 (≥ 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.
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. 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. 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.
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, and absorption from green leafy vegetables (broccoli, spinach, romaine lettuce) has 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.
See Basic Diet Orders chapter.
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).
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.
- Wright NC, Looker AC, Saag KG, et al. The recent prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine. J Bone Miner Res. 2014;29(11):2520-6. [PMID:24771492]
- Looker AC, Melton LJ, Borrud LG, et al. Lumbar spine bone mineral density in US adults: demographic patterns and relationship with femur neck skeletal status. Osteoporos Int. 2012;23(4):1351-60. [PMID:21720893]
- Woodson GC. Risk factors for osteoporosis in postmenopausal African-American women. Curr Med Res Opin. 2004;20(10):1681-7. [PMID:15462702]
- Macdonald HM, New SA, Golden MH, et al. Nutritional associations with bone loss during the menopausal transition: evidence of a beneficial effect of calcium, alcohol, and fruit and vegetable nutrients and of a detrimental effect of fatty acids. Am J Clin Nutr. 2004;79(1):155-65. [PMID:14684412]
- Berg KM, Kunins HV, Jackson JL, et al. Association between alcohol consumption and both osteoporotic fracture and bone density. Am J Med. 2008;121(5):406-18. [PMID:18456037]
- Cosman F, de Beur SJ, LeBoff MS, et al. Clinician's Guide to Prevention and Treatment of Osteoporosis. Osteoporos Int. 2014;25(10):2359-81. [PMID:25182228]
- Riggs BL, Melton LJ. Involutional osteoporosis. N Engl J Med. 1986;314(26):1676-86. [PMID:3520321]
- Bonaiuti D, Shea B, Iovine R, et al. Exercise for preventing and treating osteoporosis in postmenopausal women. Cochrane Database Syst Rev. 2002. [PMID:12137611]
- Prior JC, Barr SI, Chow R, et al. Prevention and management of osteoporosis: consensus statements from the Scientific Advisory Board of the Osteoporosis Society of Canada. 5. Physical activity as therapy for osteoporosis. CMAJ. 1996;155(7):940-4. [PMID:8925493]
- Ward KD, Klesges RC. A meta-analysis of the effects of cigarette smoking on bone mineral density. Calcif Tissue Int. 2001;68(5):259-70. [PMID:11683532]
- Cornuz J, Feskanich D, Willett WC, et al. Smoking, smoking cessation, and risk of hip fracture in women. Am J Med. 1999;106(3):311-4. [PMID:10190380]
- Qaseem A, Forciea MA, McLean RM, et al. Treatment of Low Bone Density or Osteoporosis to Prevent Fractures in Men and Women: A Clinical Practice Guideline Update From the American College of Physicians. Ann Intern Med. 2017;166(11):818-839. [PMID:28492856]
- JafariNasabian P, Inglis JE, Kelly OJ, et al. Osteosarcopenic obesity in women: impact, prevalence, and management challenges. Int J Womens Health. 2017;9:33-42. [PMID:28144165]
- Burckhardt P. Calcium revisited, part III: effect of dietary calcium on BMD and fracture risk. Bonekey Rep. 2015;4:708. [PMID:26331006]
- Feskanich D, Willett WC, Colditz GA. Calcium, vitamin D, milk consumption, and hip fractures: a prospective study among postmenopausal women. Am J Clin Nutr. 2003;77:504-511.
- Fenton TR, Tough SC, Lyon AW, et al. Causal assessment of dietary acid load and bone disease: a systematic review & meta-analysis applying Hill's epidemiologic criteria for causality. Nutr J. 2011;10:41. [PMID:21529374]
- Movassagh EZ, Vatanparast H. Current Evidence on the Association of Dietary Patterns and Bone Health: A Scoping Review. Adv Nutr. 2017;8(1):1-16. [PMID:28096123]
- Bonjour JP. Dietary protein: an essential nutrient for bone health. J Am Coll Nutr. 2005;24(6 Suppl):526S-36S. [PMID:16373952]
- Weaver CM, Gordon CM, Janz KF, et al. The National Osteoporosis Foundation's position statement on peak bone mass development and lifestyle factors: a systematic review and implementation recommendations. Osteoporos Int. 2016;27(4):1281-1386. [PMID:26856587]
- Zheng X, Lee SK, Chun OK. Soy Isoflavones and Osteoporotic Bone Loss: A Review with an Emphasis on Modulation of Bone Remodeling. J Med Food. 2016;19(1):1-14. [PMID:26670451]
- O'Keefe JH, Bergman N, Carrera-Bastos P, et al. Nutritional strategies for skeletal and cardiovascular health: hard bones, soft arteries, rather than vice versa. Open Heart. 2016;3(1):e000325. [PMID:27042317]
- Mangano KM, Sahni S, Kerstetter JE. Dietary protein is beneficial to bone health under conditions of adequate calcium intake: an update on clinical research. Curr Opin Clin Nutr Metab Care. 2014;17(1):69-74. [PMID:24316688]
- Mangano KM, Sahni S, Kiel DP, et al. Bone Mineral Density and Protein-Derived Food Clusters from the Framingham Offspring Study. J Acad Nutr Diet. 2015;115(10):1605-1613.e1. [PMID:26038297]
- Jiao L, Stolzenberg-Solomon R, Zimmerman TP, et al. Dietary consumption of advanced glycation end products and pancreatic cancer in the prospective NIH-AARP Diet and Health Study. Am J Clin Nutr. 2015;101(1):126-34. [PMID:25527756]
- Poundarik AA, Wu PC, Evis Z, et al. A direct role of collagen glycation in bone fracture. J Mech Behav Biomed Mater. 2015;52:120-130. [PMID:26530231]
- Barzilay JI, Bůžková P, Zieman SJ, et al. Circulating levels of carboxy‐methyl‐lysine (CML) are associated with hip fracture risk: the Cardiovascular Health Study. J Bone Miner Res. 2014;29(5):1061-6. [PMID:24877243]
- Lydeking-Olsen E, Beck-Jensen JE, Setchell KD, et al. Soymilk or progesterone for prevention of bone loss--a 2 year randomized, placebo-controlled trial. Eur J Nutr. 2004;43(4):246-57. [PMID:15309425]
- Ho SC, Woo J, Lam S, et al. Soy protein consumption and bone mass in early postmenopausal Chinese women. Osteoporos Int. 2003;14(10):835-42. [PMID:12920508]
- Benetou V, Orfanos P, Feskanich D, et al. Fruit and vegetable intake and hip fracture incidence in older men and women: the CHANCES Project. J Bone
- Luo Sy, Li Y, Luo H, et al. Increased intake of vegetables, but not fruits, may be associated with reduced risk of hip fracture: A meta-analysis. Sci Rep. 2016;6:19783. [PMID:26806285]
- Weaver CM, Alekel DL, Ward WE, et al. Flavonoid intake and bone health. J Nutr Gerontol Geriatr. 2012;31(3):239-53. [PMID:22888840]
- Vafa M, Soltani S, Zayeri F, et al. The relationship between sodium intake and some bone minerals and osteoporosis risk assessment instrument in postmenopausal women. Med J Islam Repub Iran. 2016;30:377. [PMID:27493921]
- Wu AM, Huang CQ, Lin ZK, et al. The relationship between vitamin A and risk of fracture: meta-analysis of prospective studies. J Bone Miner Res. 2014;29(9):2032-9. [PMID:24700407]
- Sarkis KS, Martini LA, Szejnfeld VL, et al. Low fatness, reduced fat intake and adequate plasmatic concentrations of LDL-cholesterol are associated with high bone mineral density in women: a cross-sectional study with control group. Lipids Health Dis. 2012;11:37. [PMID:22409945]
- Longo AB, Ward WE. PUFAs, Bone Mineral Density, and Fragility Fracture: Findings from Human Studies. Adv Nutr. 2016;7(2):299-312. [PMID:26980813]
- Liu H, Yao K, Zhang W, et al. Coffee consumption and risk of fractures: a meta-analysis. Arch Med Sci. 2012;8(5):776-83. [PMID:23185185]
- Sheng J, Qu X, Zhang X, et al. Coffee, tea, and the risk of hip fracture: a meta-analysis. Osteoporos Int. 2014;25(1):141-50. [PMID:24196722]
- Lee DR, Lee J, Rota M, et al. Coffee consumption and risk of fractures: a systematic review and dose-response meta-analysis. Bone. 2014;63:20-8. [PMID:24576685]
- Kanis JA, Johansson H, Johnell O, et al. Alcohol intake as a risk factor for fracture. Osteoporos Int. 2005;16(7):737-42. [PMID:15455194]
- Zhang X, Yu Z, Yu M, et al. Alcohol consumption and hip fracture risk. Osteoporos Int. 2015;26(2):531-42. [PMID:25266483]
- Avenell A, Mak JC, O'Connell D. Vitamin D and vitamin D analogues for preventing fractures in post-menopausal women and older men. Cochrane Database Syst Rev. 2014;2014(4):CD000227. [PMID:24729336]
- Uusi-Rasi K, Kärkkäinen MU, Lamberg-Allardt CJ. Calcium intake in health maintenance - a systematic review. Food Nutr Res. 2013;57. [PMID:23687486]
- Weaver CM, Alexander DD, Boushey CJ, et al. Calcium plus vitamin D supplementation and risk of fractures: an updated meta-analysis from the National Osteoporosis Foundation. Osteoporos Int. 2016;27(1):367-76. [PMID:26510847]
- Gruppen MP, Davin JC, Oosterveld MJ, et al. Prevention of steroid-induced low bone mineral density in children with renal diseases: a systematic review. Nephrol Dial Transplant. 2013;28(8):2099-106. [PMID:23640430]
- Overton ET, Chan ES, Brown TT, et al. Vitamin D and Calcium Attenuate Bone Loss With Antiretroviral Therapy Initiation: A Randomized Trial. Ann Intern Med. 2015;162(12):815-24. [PMID:26075752]
- Lazzari AA, Dussault PM, Thakore-James M, et al. Prevention of bone loss and vertebral fractures in patients with chronic epilepsy--antiepileptic drug and osteoporosis prevention trial. Epilepsia. 2013;54(11):1997-2004. [PMID:24010637]
- Maresz K. Proper Calcium Use: Vitamin K2 as a Promoter of Bone and Cardiovascular Health. Integr Med (Encinitas). 2015;14(1):34-9. [PMID:26770129]
- Stevenson M, Lloyd-Jones M, Papaioannou D. Vitamin K to prevent fractures in older women: systematic review and economic evaluation. Health Technol Assess. 2009;13(45):iii-xi, 1-134. [PMID:19818211]
- Shearer MJ, Fu X, Booth SL. Vitamin K nutrition, metabolism, and requirements: current concepts and future research. Adv Nutr. 2012;3(2):182-95. [PMID:22516726]
- Fang AP, Li KJ, Shi HY, et al. Habitual dietary calcium intakes and calcium metabolism in healthy adults Chinese: a systematic review and meta-analysis. Asia Pac J Clin Nutr. 2016;25(4):776-784. [PMID:27702721]