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Decisions to intervene when osteoporosis is diagnosed reflect a desire to prevent early or continuing bone loss, a belief that there can be an immediate impact on the patient’s well-being, and a willingness to comply with the patient’s desires. Bone densitometry can assist in the decision-making process if the patient’s age confers risk, there are no manifestations of disease, and if the decision point is prevention rather than treatment. BMD measurements can also assist in therapy when there are relative contraindications to a specific agent, and demonstrating efficacy could encourage continuation of therapy. Medicare currently reimburses costs of bone densitometry according to the conditions outlined in Table 30-6. The decision to intervene with pharmacologic therapy involves clinical judgment based on a global assessment, rather than BMD measurement alone. All currently approved therapeutic agents for the prevention and treatment of osteoporosis work by inhibiting or decreasing bone resorption.
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Adequate estrogen levels remain the single most important therapy for maintaining adequate bone density in women. Prior to 2003, estrogen replacement therapy was considered for all women with decreased bone density, absent contraindications. However, in July 2002, the Women’s Health Initiative randomized controlled primary prevention trial was stopped at a mean 5.2 years of follow-up by the Data and Safety Monitoring Board because the test statistic for invasive breast cancer exceeded the stopping boundary for the adverse effect of estrogen and progesterone versus placebo. Estimated hazard ratios were excessive for coronary heart disease, breast cancer, and strokes, but were <1.0 for colorectal cancer, endometrial cancer, and hip fracture. Therefore, careful risk assessment is needed for each patient to determine whether the improvement of risk for hip fracture (0.66) balances the risk for cardiovascular and breast disease. Contraindications to estrogen replacement therapy are listed in Table 30-7.
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Studies have been done to determine the effect of the timing of initiation and the duration of postmenopausal estrogen therapy on BMD. Current users who started estrogen therapy at menopause had the highest BMD levels, which were significantly higher than those of women who never used estrogen therapy or past users who started at menopause (with a duration of use of ≥10 years). BMD was similar for women using unopposed estrogen or estrogen plus progestin, and for current smokers or nonsmokers. Current users who started estrogen within 5 years of menopause had a decreased risk of hip, wrist, and all nonspinal fractures compared with those who never used estrogen. Long-term users who initiated therapy 5 years after menopause had no significant reduction in risk for all nonspinal fractures, despite an average duration of use of 16 years. Therefore, early initiation of estrogen with respect to menopause may be more important than the total duration of use. Estrogen initiated early in the menopausal period and continued into late life appears to be associated with the highest bone density.
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As more and more women utilize estrogen therapy, there has been increasing concern regarding its impact on breast cancer risk. The relation between the use of hormones and the risk of breast cancer in postmenopausal women was assessed in a follow-up survey of participants in the Nurses’ Health Study in 1992. The risk of breast cancer was significantly increased among women who were currently using estrogen alone or estrogen plus progestin, as compared with postmenopausal women who had never used hormones. Women currently taking hormones who had used such therapy for 5-9 years had an adjusted relative risk (RR) of breast cancer of 1.46, as did those currently using hormones who had done so for a total of 10 or more years (RR = 1.46). The addition of progestins to estrogen therapy does not reduce the risk of breast cancer among postmenopausal women.
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The only randomized trial of estrogen-progesterone therapy describes secondary prevention of coronary heart disease in postmenopausal women [Heart and Estrogen/progestin Replacement Study (HERS)] and included only women who had a prior history of cardiovascular disease. Women received either estrogen alone or estrogen plus progesterone. There was an excessive number of deaths from coronary heart disease and a threefold excess risk of venous thrombosis during the first year of the trial in women on estrogen and a small risk of stroke in women on estrogen and progesterone. Recommendations at the conclusion of the trial included not starting women who already have clinical cardiovascular disease on estrogen and progesterone therapy (ie, secondary prevention).
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B. Calcium and Vitamin D
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Calcium supplementation produces small beneficial effects on bone mass throughout postmenopausal life and may reduce fracture rates by more than the change in BMD would predict—possibly as much as 50%. Postmenopausal women receiving supplemental calcium over a 3-year period in a placebo-controlled, randomized clinical trial had stable total body calcium and BMD in the lumbar spine, femoral neck, and trochanter compared with the placebo group.
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Vitamin D increases calcium absorption in the gastrointestinal tract, so that more calcium is available in the circulation and is subsequently reabsorbed in the renal proximal tubules. There is now evidence of significant reductions in nonvertebral fracture rates from physiologic replacement of vitamin D in the elderly. Vitamin D supplementation is important in those of all ages with limited exposure to sunlight.
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Dietary calcium augmentation should be recommended to maintain lifetime calcium levels and to help prevent early postmenopausal bone loss (Table 30-8). Adults should ingest 1200 mg of elemental calcium per day for optimal bone health. Teenagers, pregnant or lactating women, women aged >50 years taking estrogen replacement therapy, and everyone aged >65 years should ingest 1500 mg of elemental calcium per day for optimal bone health. If this cannot be achieved by diet alone, calcium supplementation is recommended. Calcium preparations should be compared relative to elemental calcium content. Therefore, attention to which form the patient is ingesting is important.
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Calcitonin, a hormone directly inhibiting osteoclastic bone resorption, is an alternative for patients with established osteoporosis in whom estrogen replacement therapy is not recommended. A unique characteristic of calcitonin is that it produces an analgesic effect with respect to bone pain and, thus, is often prescribed for patients who have suffered an acute osteoporotic fracture. The American College of Rheumatology recommends treatment until the pain is controlled, followed by tapering of medication over 4—6 weeks. Calcitonin decreases further bone loss at vertebral and femoral sites in patients with documented osteoporosis but has a questionable effect on fracture frequency. Calcitonin has been shown to prevent trabecular bone loss during the first few years of menopause, but it is unclear whether it has any impact on cortical bone. Calcitonin is also thought to be effective in decreasing the fracture rate of vertebrae and peripheral bones.
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For reasons that are poorly understood, the increase in BMD associated with administration of calcitonin may be transient, or there may be the development of resistance. Therefore, calcitonin should be prescribed more acutely and other medications used for chronic management. Calcitonin can be provided in two forms. Nasal congestion and rhinitis are the most significant side effects of the nasal form. The injectable formulation has gastrointestinal side effects and is less convenient than the nasal preparation. The increase in bone density observed by this therapy is significantly less than that achieved by bisphosphonates or estrogen and may be limited to the spine, but it still has recognized value in reducing risk of fracture.
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The FDA is currently reviewing prescribing recommendations for calcitonin and new guidelines are forthcoming in the near future.
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Bisphosphonates are antiresorptive agents and effective for preventing bone loss associated with estrogen deficiency, glucocorticoid treatment, and immobilization. Antiresorptive agents improve the quality of bone by preserving trabecular architecture. They may increase bone strength by methods other than by increasing BMD. All bisphosphonates act similarly on bone in binding permanently to mineralized bone surfaces and inhibiting osteoclastic activity. Thus, less bone is degraded during the remodeling cycle. First-, second-, and third-generation bisphosphonates are now available (alendronate, risedronate, and ibandronate). Because food and liquids can reduce the absorption of bisphosphonates, they should be given with a glass of plain water 30 minutes before the first meal or beverage of the day. Patients should not lie down for at least 30 minutes to lessen the chance of esophageal irritation. In addition, patients should consider taking supplemental calcium and vitamin D if their dietary intake is inadequate.
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Bisphosphonates are of comparable efficacy to hormone replacement therapy in preventing bone loss and have a demonstrated positive effect on symptomatic and asymptomatic vertebral fracture rate as well as on nonvertebral fracture rate (forearm and hip). More than 4 years of treatment would be needed in women with low bone density (T score ≥ −2.0), but without preexisting fractures, to substantially reduce the risk of clinical fracture.
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In clinical trials, alendronate was generally well tolerated and no significant clinical or biological adverse experiences were observed. Alendronate appears to be effective at doses of 5 mg daily in preventing osteoporosis induced by long-term glucocorticoid therapy. In placebo-controlled studies of men and women (aged 17–83) who were receiving glucocorticoid therapy, femoral neck bone density and the bone density of the trochanter and total body increased significantly in patients treated with alendronate.
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Alendronate appears to be a safe, well-tolerated, and lower-cost agent for the osteoporosis and is a good first-line treatment. Some small-scale studies suggest an additional benefit of adding alendronate to hormone replacement therapy, and ongoing studies should provide additional information. However, all of the bisphosphonates accumulate over time in bone, and further research is needed to determine their long-term impact as well as their potential for use in premenopausal women and men.
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Risedronate is a pyridinyl bisphosphonate approved as treatment for several metabolic bone diseases in 2000. In doses of 5 mg daily, risedronate reduces the incidence of vertebral fractures in women with two or more fractures by rapidly increasing BMD at sites of cortical and trabecular bone. In a randomized trial of 2458 postmenopausal women with diagnosed osteoporosis, participants were treated with either 2.5 mg or 5 mg of risedronate or placebo as well as calcium supplementation and cholecalciferol if they had low baseline 25-hydroxyvitamin D levels. The 2.5-mg dose was found to be ineffective in other trials and was discontinued. After 3 years of treatment, the 5-mg risedronate group showed a 41% reduction in risk of new vertebral fractures and a 39% reduction in incidence of nonvertebral fractures.
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In a large, prospective, hip fracture prevention trial of elderly women, risedronate was shown to significantly reduce the risk of hip fracture in women with osteoporosis. Bisphosphonates should be prescribed for 3–4 years in women with osteoporosis and low bone density.
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Ibandronate is currently approved by the Food and Drug Administration (FDA) for the treatment and prevention of osteoporosis in postmenopausal women. Over a 3-year period, ibandronate was shown to decrease the incidence of new vertebral fractures by 52% and to increase BMD at the spine by 5%. It can be administered daily or once a month.
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Zoledronic acid was approved by the FDA in 2011 and is marketed as Reclast. A single annual intramuscular dose of 5 mg was studied in 1367 patients. Femoral neck BMD increasedby 3.7% above placebo 3 years after a single dose of zoledronic acid. Clinical fracture rates were reduced by 32% in patients receiving single infusions and 34% in those receiving three infusions over a 3-year period. There is no general agreement regarding how long to wait before repeating the injection.
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Strontium ranelate is approved and used in the European Union and is effective in treating osteoporosis in both men and women.
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Reid
IR, Black
DM, Eastell
R
et al.. Reduction in the risk of clinical fractures after a single dose of zoledronic acid 5 milligrams. J Clin Endocrinol Metab. 2013;98(2):557–563.
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More than 150 million bisphosphonate scripts were dispensed between 2005 and 2009. Postmarketing surveillance reports atypical femoral fracture, jaw osteonecrosis, and esophageal cancer. FDA reviews of alendronate, residronate, and zoledronic acid reveal rare side effects of 1 in 1000 to 10,000 users. Little additional benefit in fracture prevention is seen after 3–5 years of use, except for vertebral fractures.
+
Compston
J, Bowring
C, Cooper
A
et al.. Diagnosis and management of osteoporosis in postmenopausal women and older men in the UK: National Osteoporosis Guideline Group (NOGG) update 2013; Maturitas (2013) (available at
http://dx.doi.org/10.1016/j.maturitas.2013.05.013).
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Whitaker
M, Guo
J, Kehoe
T
et al.. Bisphosphonates for osteoporosis—where do we go from here? N Engl J Med. 2012;366:2048–2051.
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E. Selective Estrogen Receptor Modulators
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Raloxifene was the first drug to be studied from a new class of drugs termed selective estrogen receptor modulators. This drug has a mixed agonist-antagonist action on estrogen receptors: specifically, estrogen agonist effects on bone and antagonist effects on breast and endometrium. Its discovery evolved from a structural rearrangement of the antiestrogen tamoxifen, although it is structurally very different. It blocks estrogen in a manner similar to tamoxifen, while also binding and stimulating other tissue receptors to act like estrogen. Raloxifene inhibits trabecular and vertebral bone loss in a manner similar, but not identical, to estrogen (ie, by blocking the activity of cytokines that stimulate bone resorption).
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Raloxifene therapy results in decreased serum total and low-density lipoprotein (LDL) cholesterol without any beneficial effects on serum total high-density lipoprotein (HDL) cholesterol or triglycerides. Reported side effects of raloxifene are vaginitis and hot flashes. Investigators in the Multiple Outcomes of Raloxifene (MORE) trial of >7000 postmenopausal, osteoporotic women over 3 years showed a decreased risk of breast cancer in those already at low risk for the disease. The study results were analyzed separately for women presenting with preexisting fracture. Although treatment effectiveness was similar in both groups, the absolute risk of fractures in the group with preexisting fractures was 4.5 times greater than in the group with osteoporosis, but no preexisting fracture (21% vs 4.5%). Thus, it is important to identify and treat patients at higher risk. Studies of women at higher risk for breast cancer are currently under way.
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A summary of overall treatment strategies is given in Table 30-9, and guidelines for dosing the pharmacologic agents are given in Table 30-10. Table 30-11 summarizes the risks and benefits of osteoporosis therapy.
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Fluoride increases bone formation by stimulating osteoblasts and increasing cancellous bone formation in patients with osteoporosis. However, the bone is formed only in the spine and is abnormal—irregularly fibrous and woven with lacunae of low mineral density. Cessation of therapy resulted in rapid loss of much of the bone formed during treatment. The major side effect of fluoride therapy is gastric distress, an effect that is thought to be related to the direct effect of hydrofluoric acid on the gastric mucosa. Fluoride is also associated with joint pain and swelling. For these reasons, sodium fluoride is not routinely used for treatment of osteoporosis and does not have FDA labeling for this indication.
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Anabolic therapy produces some increase in bone mass. Teriparatide (PTH 1-34), marketed under the trade name Forteo, or recombinant parathyroid hormone, is FDA-approved for the treatment of osteoporosis in perimenopausal women who are at high risk for fracture. Teriparatide also has FDA labeling for increasing bone mass in men with primary or hypogonadal osteoporosis who are at high risk for fracture. Unlike antiresorptive agents, teriparatide stimulates new bone formation. There are some concerns regarding extended use of teriparatide because of the long-term effects on multiple organ systems (ie, significant hepatotoxicity, reduced HDL, and elevated LDL cholesterol).
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Teriparatide is the first approved agent for the treatment of osteoporosis that stimulates new bone formation. It is administered once a day by injection (20 μg/d) in the thigh or abdomen. Patients treated with 20 μg/d of teriparatide, along with calcium and vitamin D supplementation, had statistically significant increases in BMD at the spine and hip when compared with patients receiving only calcium and vitamin D supplementation. Clinical trials also demonstrated that teriparatide reduced the risk of vertebral and nonvertebral fractures in postmenopausal women. The effects of teriparatide on fracture risk have not been studied in men.
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Of note, osteosarcoma developed in animals in early studies, and the possibility that humans treated with teriparatide may face an increased risk of developing this cancer cannot be ruled out. This safety issue is highlighted in a black box warning in the drug label for health professionals and explained in a brochure for patients. Children and adolescents with growing bones and patients with Paget disease of the bone have a higher risk for developing osteosarcoma and should not be treated with this agent. Because the effects of long-term treatment with teriparatide are not known, therapy for >2 years is not recommended.
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Testosterone replacement is acceptable therapy for many of the causes of hypogonadism in men [eg, Klinefelter syndrome, isolated gonadotropin deficiency (Kallmann syndrome)].
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Denosumab, a fully human, monoclonal antibody that inhibits Rank Ligand—a key modulator of osteoclast formation, function, and survival—was approved by the FDA in 2012. The FREEDOM study of 7808 postmenopausal women with osteoporosis compared 60 mg of denosumab with placebo given every 6 months for 36 months. DXA and quantitative CT scans were used for monitoring. Denosumab significantly increased BMD (bone mineral content) and does not appear to delay fracture healing. Denosumab usage warrants caution in the presence of hypocalcemia; serious side effects include skin infections, osteonecrosis of the jaw, and suppression of bone turnover, which could include atypical femoral fracture after long-term use.
+
Adami
S. J Bone Joint Surg Am. 2012;94:2113–2119.
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Simon
JA, Recknor
C, Moffett
AH
et al.. Impact of
denosumab on the peripheral skeleton of postmenopausal women with osteoporosis.
Menopause. 2013;20(2):130–137.
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G. Complementary and Alternative Therapies
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Nutraceuticals are now being used more frequently by patients to promote bone health. There is a paucity of data confirming the benefit of these products, but likewise no evidence of harm. The most common nutraceuticals used for bone health are phytoestrogens (isoflavones, lignins, and coumestans), vitamin A, the B vitamins [B2 (folate) and B12], vitamin K, magnesium, and omega-3 fatty acids.
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Evidence from animal studies suggests a beneficial effect of phytoestrogens on bone, but long-term human studies are lacking. Epidemiologic evidence that Asian women have a lower fracture rate than white women, even though the bone density of Asian women is less than that of African-American women, promotes consideration of the impact of nutrition. It is possible that high soy intake contributes to improved bone quality in Asian women. A comparison study of a soy protein and high isoflavone diet versus a milk protein diet or medium isoflavone and soy protein diet demonstrated that only those receiving the higher isoflavone preparation were protected against trabecular (vertebral) bone loss.
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A topical form of natural progesterone derived from diosgenin in either soybeans or Mexican wild yam has been promoted as a treatment for osteoporosis, hot flashes, and premenstrual syndrome, and a prophylactic against breast cancer. However, eating or applying wild yam extract or diosgenin does not produce increased progesterone levels in humans because humans cannot convert diosgenin to progesterone.
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All patients should be encouraged to maintain a bone-healthy diet. This includes reducing soft drink and sodium consumption, eating potassium-rich foods, encouraging iron and folate supplementation in adolescent females and women of childbearing age, and vitamin B12 supplementation in persons aged 50 years and vitamin D supplementation in the elderly, in dark-skinned people, and in those with low UVB exposure.
+
Nieves
J. Nutraceuticals: effects on bone metabolism. Talk presented at 8th International Symposium on Osteoporosis Meeting, Washington, DC, April 1–5 , 2009.
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Weaver
C. Nutrition an osteoporosis. Talk presented at 8th International Symposium on Osteoporosis Meeting. Washington, DC, April 1–5 , 2009.
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H. Glucocorticoid-Induced Osteoporosis
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Glucocorticoids are widely used in the treatment of many chronic diseases, particularly asthma, chronic lung disease, and inflammatory and rheumatologic disorders, and in those who have undergone organ transplantation. The risk that oral steroid therapy poses to bone mineral density, among other side effects, has been known for some time. As a result, clinicians have eagerly substituted inhaled steroids in an endeavor to protect the patient from unwanted negative steroid effects. Recent evaluations of the effects of inhaled glucocorticoids on bone density in premenopausal women demonstrated a dose-related decline in bone density at both the total hip and the trochanter. Women with asthma were enrolled and were divided into three groups: those using no inhaled steroids, those using four to eight puffs per day, and those using more than eight puffs per day at 100 μg per puff. No dose-related effect was noted at the femoral neck or the spine. Serum and urinary markers of bone turnover or adrenal function did not predict the degree of bone loss. To achieve the best possible outcome for the patient, given the potentially devastating effects of systemic steroids, therapy to combat the steroids should begin as soon as the steroids are begun. See Table 30-9 for specific guidelines.
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American College of Rheumatology recommendations are to initiate bisphosphonate use in glucocorticoid-induced osteoporosis and to initiate therapy if: (1) the glucocorticoid use will equal or exceed 3 months, (2) if the patient has a T score of less than –1, or (3) if the patients receiving long-term glucocorticoid therapy have had fractures on, or cannot tolerate hormone replacement therapy.
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ACR Ad Hoc Committee on GIO. Arthritis Rheum. 2001;44:1496–1503
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Israel
E
et al.. Effects of inhaled glucocorticoids on bone density in premenopausal women.
New Engl J Med. 2001; 345:941.
[PubMed: 11575285]
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Potter
SM
et al.. Soy protein and isoflavones: their effects on blood lipids and bone density in postmenopausal women.
Am J Clin Nutr. 1998; 68:(suppl):1375S.
[PubMed: 9848502]
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Saag
KG
et al..
Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis: glucocorticoid-Induced Osteoporosis Intervention Study Group.
N Engl J Med. 1998; 339:292.
[PubMed: 9682041]
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Summary recommendations for postmenopausal women and men aged ≥50 years are to: (1) counsel on the risk of osteoporosis and fractures, (2) check for secondary causes, (3) advise on adequate calcium and vitamin D, (4) recommend regular exercise, and (5) advise on avoidance of tobacco and alcohol intake. In women aged ≥65 years and men aged ≥70 years, recommend BMD testing. In postmenopausal women between the ages of 50 and 69, recommend BMD testing based on the risk factor profile. Furthermore, when a patient has already experienced a fracture, recommend BMD to determine the severity of the disease.