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The primary goal of osteoporosis treatment is fracture prevention in women who have low BMD or additional risk factors for fracture (Fig. 22-1). Toward this end, therapy aims to stabilize or increase BMD. Treatment includes lifestyle changes and often pharmacologic therapy. The key lifestyle modifications that can decrease fracture risks of in postmenopausal women include regular weight-bearing exercise and a balanced diet with adequate calcium and vitamin D. Factors for patients to avoid include smoking, an excessively low body weight, excessive alcohol intake, and fall risks at home (Christiansen, 2013).
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With pharmacologic therapy, several organizations offer guidelines. The National Osteoporosis Foundation (NOF) (2014), American Association of Clinical Endocrinologists (AACE) (Watts, 2010), and North American Menopause Society (NAMS) (2010) recommend starting therapy for: (1) all postmenopausal women with total hip, femoral neck, or spine T-scores at or below –2.5; (2) for those with an osteoporotic vertebral or hip fracture; and (3) all postmenopausal women with total hip or spine T-scores from –1.0 to –2.5 who have one or more additional risk factors for fracture, such as those in Table 21-8.
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Drugs prescribed for fracture prevention attempt to restore and balance bone remodeling by: (1) reducing bone resorption, termed antiresorptive agents, or (2) stimulating bone formation, termed anabolic agents. Most of the bone-active agents currently available in the United States inhibit bone resorption. Estrogen, SERMs, bisphosphonates, denosumab, calcitonin, and vitamin D each have antiresorptive properties (Table 22-4). All have been shown to halt bone loss, and most also increase BMD. Improvement in BMD with therapeutic intervention varies according to bone composition. Therapies that prevent bone resorption will act most quickly on bone that has high trabecular content and rapid turnover, such as the vertebrae. Alternatively, the impact of drug therapies on the hip may be delayed because the hip is composed of approximately 50 percent trabecular and 50 percent cortical bone (Fig. 21-5). In contrast to these antiresorptive agents, recombinant parathyroid hormone (PTH 1–34), known as teriparatide, is anabolic and leads to BMD increases.
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For osteoporosis, each agent differs in its indication for prevention, for treatment, or both. HT is indicated for the prevention of osteoporosis. Bisphosphonates and SERMs can be used for prevention and for treatment. Calcitonin and teriparatide are approved for treatment. Denosumab is a monoclonal antibody to the receptor activator of nuclear factor (RANK) ligand and is approved for osteoporosis treatment.
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Estrogen and Progesterone Replacement
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As estrogen levels decline, bone-remodeling rates increase and favor bone resorption over bone formation. In observational studies, HT reduces osteoporosis-related fractures by approximately 50 percent when started soon after menopause. Continued long term, HT significantly decreases fracture rates in women with established disease (Tosteson, 2008). Results from 57 randomized, placebo-controlled trials show that HT reduces the rate of bone resorption and results in an increase in BMD (Wells, 2002). The WHI controlled trials confirmed a significant 33-percent reduction in hip fractures in healthy postmenopausal women receiving HT after an average follow-up of 5.6 years. Notably, hip fracture reduction was not limited to women with osteoporosis, as in trials of other pharmacologic agents (The Women’s Health Initiative Steering Committee, 2004). Even very low estrogen doses combined with calcium and vitamin D produce significant increases in BMD compared with placebo (Ettinger, 2004; Prestwood, 2003). Specifically, oral daily 0.2-mg doses of estradiol; 0.3-mg doses of CEE; or transdermal estradiol patch delivering 0.014 mg/d are suitable.
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Unfortunately, this preventive effect is lost rapidly following HT discontinuation (Barrett-Connor, 2003). Women participating in the National Osteoporosis Risk Assessment (NORA) trial who had discontinued estrogen therapy within the 5 years preceding the study demonstrated a significantly higher hip fracture risk than did women who had never received estrogen therapy. In addition, current HT users in the NORA trial had a 40-percent reduction in hip fractures, which was lost by past users. Thus, fracture risk and the potential need for an alternative therapy is ideally assessed when women discontinue HT.
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The drug that combines CEE with the SERM bazedoxifene is indicated to alleviate vasomotor symptoms and prevent postmenopausal bone loss. In the randomized SMART trials noted earlier, investigators found a significantly increased adjusted mean percentage BMD change in the lumbar spine from baseline to 24 months in those taking BZA plus CEE compared with women using placebo (Lindsay, 2009). Findings were similar for total hip BMD. Moreover, the FDA-approved dose of CEE (0.45 mg) plus BZA (20 mg) does not cause a change in breast density or endometrial thickness compared with placebo (Pinkerton, 2014).
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This SERM is approved for the prevention and treatment of osteoporosis and to reduce the risk of invasive breast cancer. It activates estrogen receptors in the bone but does not appear to activate those in the breast or uterus.
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Of bone loss sites, raloxifene may be most appropriate for prevention and treatment of vertebral disease. For example, raloxifene prevented vertebral fractures in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, which enrolled 7705 postmenopausal women with osteoporosis. The beneficial effects of oral raloxifene, 60 mg/d, appeared rapidly, and clinical vertebral fracture risk was reduced by 68 percent following the first year of therapy. In addition, this effect was sustained over time. At 4 years of treatment, dosages of 60 mg daily led to a 36-percent reduction in fractures, and 120 mg each day produced a 43-percent decline (Delmas, 2002; Ettinger, 1999). However, in the MORE trial, Ettinger and associates (1999) reported that raloxifene therapy compared with placebo was not associated with significant reductions in nonvertebral fracture risks at 3 and 4 years. A more recent retrospective cohort study showed that patients treated with alendronate and raloxifene had similar adjusted fracture rates in up to 8 years of compliant treatment (Foster, 2013).
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In 2012, Chung and colleagues showed that raloxifene, but not bisphosphonates, significantly suppressed circulating concentration of sclerostin, an inhibitor of bone formation, suggesting that sclerostin may in part mediate the action of estrogen on bone metabolism.
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In addition to its bone effects, raloxifene may protect against breast cancer, as suggested by observational studies of various clinical trials (Barrett-Connor, 2006). The incidence of breast cancer was evaluated as a secondary end point in the MORE trial. Investigators found that raloxifene was associated with a 65-percent relative risk reduction in all breast cancers. Of specific breast cancer subtypes, they noted a 90-percent reduction in estrogen receptor–positive cancers, a 12-percent reduction in estrogen receptor–negative breast cancers, and a 76-percent relative risk reduction in invasive breast cancer.
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Raloxifene may not have the same increased cardiovascular risk profile as estrogen. In a MORE post hoc analysis, 4 years of raloxifene therapy had no adverse effect on cardiovascular events in the overall cohort. Advantageously, it did result in a significant 40-percent reduction in the incidence of cardiovascular events among a subgroup of women with increased cardiovascular risk (Barrett-Connor, 2002).
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Of side effects, hot flushes are associated with raloxifene therapy, although the incidence is low (Cohen, 2000). In addition, raloxifene, 60 mg daily for 4 years, has been associated with an increased risk of thromboembolic events. In one study, the relative risk associated with any dosage of raloxifene was 2.76 for deep-vein thrombosis, 2.76 for pulmonary embolism, and 0.50 for retinal vein thrombosis (Delmas, 2002). It is therefore contraindicated in patients with a history of VTE and is used with caution in women with hepatic or moderate to severe renal impairment.
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Nonhormonal Antiresorptive Agents
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Four bisphosphonates are currently available and include alendronate (Fosamax, Binosto), risedronate (Actonel, Atelvia), ibandronate (Boniva), and zoledronate (Reclast). The first three are taken orally, but zoledronate is an intravenous infusion. These agents chemically bind to calcium hydroxyapatite in bone (Figs. 22-2 and 22-3). They decrease bone resorption by blocking the function and survival but not the formation of osteoclasts (Diab, 2012; Russell, 2008).
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The oral bisphosphonates display poor bioavailability and therefore are taken on an empty stomach with adequate water for proper dissolution and absorption. In general, these agents have a favorable overall safety profile, and adverse event rates are comparable with placebo (Black, 1996; Harris, 1999). However, bisphosphonates may cause upper gastrointestinal inflammation, ulceration, and bleeding (Lanza, 2000). Thus, to aid delivery to the stomach and reduce the risk of esophageal irritation, dosing instructions are reinforced with each patient. First, bisphosphonates are taken in the morning with a full glass of water. During the 30 minutes following administration, no other food or beverages are consumed. Finally, women must remain upright (sitting or standing) for at least 30 minutes after ingesting the drug.
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In terms of long-term safety, concerns about two uncommon adverse events have emerged: osteonecrosis of the jaw (ONJ) and atypical femur fractures (AFFs) (Diab, 2013). ONJ is defined as exposed necrotic bone in the maxillofacial region that fails to heal after 8 weeks. It can be associated with pain, paresthesia, soft tissue ulceration and swelling, and loosening of teeth. This can develop spontaneously but is generally associated with invasive dental procedures. ONJ has been described in patients receiving chronic bisphosphonate therapy for osteoporosis treatment but appears to be much more common in cancer patients receiving higher-dose bisphosphonates (Khosia, 2007).
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AFFs are stress fractures that are frequently bilateral, are typically associated with minimal or no trauma, and are heralded by prodromal pain in the fracture region (Dell, 2012). One case-controlled study found that longer bisphosphonate use (5 to 9 years) was associated with a greater risk of AFFs compared with shorter use (<2 years) (Meier, 2012). One review showed that bisphosphonate exposure was associated with an increased risk of AFF and an adjusted risk ration of 1.70 (Gedmintas, 2013). However, in this analysis, the large variation in relative risks reported in the different studies suggests significant heterogeneity in the patient populations.
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No causal relationship has been established between prolonged bisphosphonate exposure and either of these outcomes. Even though the risks of ONJ and AFF may increase after 5 years of bisphosphonate therapy, the likelihood remains low. The FDA suggests reevaluating individually the need for continuing bisphosphonate therapy beyond 3 to 5 years (Whitaker, 2012). A “drug holiday” may be considered because of the unique pharmacokinetics of bisphosphonate. These agents accumulate in the skeleton to create a reservoir that continues to be released for months or years after treatment. Although this provides some residual benefit in terms of fracture reduction after an initial 3- to 5-year course of therapy, continuing treatment for 10 years seems to be a better choice for high-risk patients. If a drug holiday is advised, risk is reevaluated sooner for drugs with lower skeletal affinity. Thus, reassessment may be prudent after 1 year for risedronate, 1 to 2 years for alendronate, and 2 to 3 years for zoledronate (Diab, 2014).
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This bisphosphonate is approved for the treatment and prevention of osteoporosis. Alendronate has been shown to reduce the risk of vertebral fractures in postmenopausal women with low BMD or osteoporosis, either with or without existing vertebral fractures (Black, 1996). Alendronate also reduces nonvertebral fracture risk in women with osteoporosis. Among women with osteoporosis who participated in the Fracture Intervention Trial (FIT), the risk of nonvertebral fractures was reduced by month 24. In addition, the effects of alendronate are sustained. For example, women who used alendronate for 5 years and then discontinued use for a subsequent 5 years had nonvertebral fracture rates comparable to those of women using the drug for 10 years (Black, 2006; Bone, 2004).
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This bisphosphonate is an effective agent in the prevention and treatment of postmenopausal osteoporosis. The strongest data supporting its efficacy stem from the Vertebral Efficacy with Risedronate Therapy (VERT) trials, conducted multinationally and also in North America. In the VERT multinational trial, Reginster and coworkers (2000) showed that risedronate reduced the risk of new vertebral fractures by 61 percent at 1 year and by 49 percent at 3 years of use. Moreover, both VERT trials found significant reductions in vertebral fractures as early as 6 months after initiation of risedronate therapy (Roux, 2004). Two extensions of these trials have provided evidence of sustained efficacy. The continuation of risedronate therapy for 2 additional years (5 years total) in the multinational VERT study was associated with a 59-percent reduction in new vertebral fractures compared with placebo.
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This bisphosphonate is approved for the prevention and treatment of postmenopausal osteoporosis. Ibandronate is an effective agent, and data from the Oral Ibandronate Osteoporosis Vertebral Fracture Trial in North America and Europe (BONE) trial showed that daily ibandronate lowered incident vertebral fracture risk by 62 percent (Chesnut, 2004). To improve compliance, this drug was evaluated as a once-monthly therapy. Once-monthly oral ibandronate is at least as effective and well tolerated as daily treatment (Miller, 2005; Reginster, 2006). Moreover, once-monthly administration may be more convenient and thereby improve compliance rates.
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This bisphosphonate is approved for the prevention and treatment of postmenopausal osteoporosis. Zoledronate is effective, and data from the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial showed that yearly zoledronate infusion lowered incident vertebral fracture risk by 70 percent compared with placebo (Black, 2007).
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This is a fully human monoclonal antibody to RANK ligand, which is described and illustrated in Chapter 21. To summarize, denosumab’s binding to RANK ligand inhibits osteoclast development and activity. This in turn decreases bone resorption and increases BMD. In a manufacturer-sponsored trial, 7868 women randomly received either denosumab or placebo subcutaneously every 6 months for 3 years (Cummings, 2009). Relative risk for new radiographically diagnosed vertebral fractures was 68-percent lower in the denosumab group. The risk for hip fractures was 40-percent lower in the denosumab group. Overall incidence of significant adverse events was similar between groups.
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The polypeptide hormone calcitonin decreases the rate of bone absorption by inhibiting resorptive activity in osteoclasts. Calcitonin is a protein, and as such, oral administration leads to its digestion. For this reason, it is delivered as an injection or nasal spray (Fortical, Miacalcin). Salmon calcitonin nasal spray has been associated with a reduction in vertebral fracture risk among postmenopausal women with osteoporosis. In the Prevent Recurrence of Osteoporotic Fractures (PROOF) study, calcitonin nasal spray, 200 IU administered daily for up to 5 years reduced the risk of vertebral fractures by 33 percent compared with placebo. However, vertebral fracture reduction was not seen at lower (100 IU/d) or higher (400 IU/d) dosages (Chesnut, 2000). Moreover, in this study, calcitonin failed to produce significant reductions in nonvertebral fracture.
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Some observational data suggest that calcitonin has an analgesic effect independent of its effect on bone (Häuselmann, 2003; Ofluoglu, 2007). This analgesic effect may make this agent particularly useful as an adjunct to other therapies for osteoporosis in women with painful, symptomatic fracture (Blau, 2003). Injectable or intranasal calcitonin is associated with an 8- to 10-percent incidence of nausea or gastric discomfort and a 10-percent incidence of local site reactions. These symptoms tend to decrease in severity with continued use. Nasal symptoms such as rhinitis occur in 3 percent of patients treated with intranasal calcitonin (Cranney, 2002).
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Recombinant parathyroid hormone (PTH 1–34), known as teriparatide, is given by daily subcutaneous injection and is approved by the FDA for the treatment of postmenopausal women with established osteoporosis, who are at high risk for fracture. Teriparatide (Forteo) increases osteoblast numbers and activity by recruiting new cells and reducing apoptosis of differentiated osteoblasts. At low daily doses of teriparatide, the anabolic effects of PTH predominate. This is in contrast to the catabolic effects generally associated with long-term, higher-dose, and chronic exposure to PTH.
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Clinical studies indicate that teriparatide increases bone quality by increasing bone density, turnover, and size (Rubin, 2002). Moreover, improvements in microarchitectural elements are evident in both cancellous and cortical regions. In women with postmenopausal osteoporosis, teriparatide, 20 or 40 μg/d, administered for approximately 21 months, was associated with 65-percent and 69-percent reductions in vertebral fractures, and 35-percent and 40-percent reductions in nonvertebral fractures, respectively (Neer, 2001).
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Similar findings were reported in a study of 52 women treated with concomitant teriparatide and HT compared with HT alone (Lindsay, 1997). In this study, at the end of 3 years, increases in vertebral, total hip, and total body BMD were 13.4 percent, 4.4 percent, and 3.7 percent, respectively, in the combined treatment group. The addition of alendronate to teriparatide, however, does not appear to enhance effects on BMD (Gasser, 2000). The effects of combination use of PTH with other bisphosphonates are not known.
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In general, PTH is safe and well tolerated, although additional data from long-term studies are needed. The most frequent treatment-related adverse events in clinical trials of teriparatide were dizziness, leg cramps, nausea, and headache. Toxicity studies with rats have shown an increased risk of osteosarcoma. However, there are significant differences in bone metabolism between rats and humans, and the applicability of rat data to humans is unclear. That said, a black box warning has been included on the product labeling in the United States, and teriparatide use is avoided by patients at increased risk for skeletal malignancy. Use for more than 2 years is not recommended due to the potential for side effects (Tashjian, 2002).
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In sum, denosumab seems to be as effective as teriparatide and zoledronate. Osteonecrosis of the jaw and fragility fractures associated with long-term bisphosphonate use are unlikely to be linked to short-acting agents such as denosumab. Because denosumab is an antibody, its potential to affect the immune system requires scrutiny. Long-term adherence to oral bisphosphonate therapy is often poor, making the relative ease of biannual injections attractive. Although teriparatide and intravenous bisphosphonates are expensive, weekly oral alendronate is available at low cost as a generic. Clinically, cost will likely play a central role in determining how these agents are selected.
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Nonpharmacologic Therapy
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Nonpharmacologic interventions are cornerstones of osteoporosis prevention and include dietary modifications, exercise programs, fall prevention strategies, and education. Of these, adequate daily calcium intake is essential for bone maintenance. For women aged 31 to 50 years, the recommended dietary reference intake (DRI) is 1000 mg daily, and for those 51 years and older, 1200 mg is recommend daily. Ideally, these DRIs are obtained through diet alone, but supplementation is used to attain these levels if needed (Institute of Medicine, 2010; Prentice, 2013). Few women meet these goals, and calcium deficiency is widespread. For example, more than 90 percent of women fail to take in enough dietary calcium to meet DRIs put forth by the Institute of Medicine. Although poor calcium intake is observed at all ages, it appears to be most common among older individuals. Specifically, fewer than 1 percent of women 71 years or older actually meet recommended goals.
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Calcium supplementation combined with vitamin D administration has been associated with reduced bone loss and decreased risk for fractures in several prospective studies (Chapuy, 1992; Dawson-Hughes, 1997; Larsen, 2004). Prentice and associates (2013) examined the health benefits and risk of calcium and vitamin D supplementation using data from the WHI. This showed a substantial reduction in hip fracture risk. Notably, supplementation must be continued long term for efficacy to be sustained.
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The DRI of vitamin D is 600 IU daily for a postmenopausal woman who is not at high risk for fractures or falls. For persons who have a high risk of osteoporosis or who are older than 70, 800 IU daily is recommended (Institute of Medicine, 2010). As with calcium, the prevalence of vitamin D deficiency is high, especially in the elderly. Deficiency leads to poor calcium absorption, secondary hyperparathyroidism, increased bone turnover, increased rates of bone loss, and, if severe, impaired bone mineralization. In addition, vitamin D deficiency causes muscle weakness and is associated with an increase in rates of falls. Vitamin D supplementation can reverse many of these effects and significantly reduce falls and hip fractures (Dawson-Hughes, 1997).
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The metabolite 25-hydroxyvitamin D is considered to be the best clinical measure of vitamin D stores (Rosen, 2011). Vitamin D deficiency is defined as a 25-hydroxyvitamin D serum level below 10 ng/mL. Vitamin D insufficiency is a serum level of 25-hydroxyvitamin D between 10 and 30 ng/mL.
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A relationship between protein intake and BMD has been reported, but a relationship with fractures has not been described. Using data from the Third National Health and Nutrition Examination Survey (NHANES III), Kerstetter and colleagues (2000) demonstrated a significant association between protein intake and total femur BMD among non-Hispanic white women aged 50 years and older. Moreover, protein supplementation (20 g/d) five times weekly for 6 months following hip fracture was associated with a 50-percent reduction in femoral bone loss at 1 year compared with placebo.
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Although no specific recommendations regarding protein intake can be made based on the limited data available, it seems prudent for clinicians to ensure that their patients eat healthy diets that provide the daily DRI of protein. As put forth by the Institute of Medicine, diets ideally contain at least 46 g/d for women (Dawson-Hughes, 2002). There may be upper limits for desirable protein intake as well. Excess urinary calcium excretion has been observed in association with the large acid loads delivered by very-high-protein diets (Barzel, 1998).
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Caffeine consumption does not appear to influence bone health in postmenopausal women who maintain an adequate daily intake of calcium and vitamin D. However, one longitudinal study showed that even moderate amounts of caffeine (two to three servings of coffee daily) may lead to bone loss in women with low calcium intake (<800 mg/d) (Harris, 1994).
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Calcium reabsorption is directly proportional to sodium reabsorption in the renal tubule. Accordingly, increases in dietary sodium have been observed to cause increases in urinary calcium excretion and corresponding increases in biochemical markers of bone turnover. Specifically, a relationship between high sodium intake (>1768 mg/d) and lower BMD has been described (Sellmeyer, 2002). This sodium effect appears to be independent of calcium intake and activity levels. As with caffeine, sodium intake moderation is a reasonable precautionary measure until this relationship is fully understood.
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Small but statistically significant increases in BMD have been observed in postmenopausal women participating in exercise programs, including aerobic exercise and resistance training (heavy weight with few repetitions). One metaanalysis of 43 RCTs concluded that lower limb resistance exercise was most effective for femur neck BMD, and combination exercise programs were most effective for vertebral BMD (Howe, 2011). Another analysis that focused on walking as exercise showed a benefit for femur neck BMD (Ma, 2013).
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Although an increase in bone density may occur, especially at the sites at which the exercise is directed, benefits of exercise may likely also be due to factors other than greater BMD (Carter, 2002). For example, an association between exercise and reduced falls has been reported. Improvements in balance, stronger muscles, better muscle tone, and stronger, more flexible bone all undoubtedly contribute to fracture reduction.
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Falls are responsible for more than 90 percent of hip fractures (Carter, 2002). Sideways falls appear to be the most detrimental and were independently associated with hip fracture in a study by Greenspan and associates (1998). Therefore, fall prevention is essential for women with osteopenia or osteoporosis. Living conditions are modified to minimize falls by reducing clutter and implementing nonslip tiles, rugs with nonskid backing, and night lights.
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Hip protector padding was also initially thought to reduce hip fractures in elderly adults. However, one Cochrane database analysis indicates that the effect of hip protectors to lower hip fracture risk is small, and compliance is low (Santesso, 2014). Falls and fractures often occur at night, when women are likely to have taken off their hip protectors. This may result from the bulkiness of hip protectors, which are uncomfortable to wear while sleeping (van Schoor, 2003).