Osteoporosis is a systemic bone disorder characterized by low bone mass and microarchitectural deterioration of bone tissue that results in an increase in bone fragility and susceptibility to fracture. Osteoporosis should be considered a diagnosis of exclusion because often there are multiple etiologies for bone loss and these underlying secondary causes should first be treated.

Epidemiology

One in two women and one in four men >50 years will have an osteoporosis-related fracture in their lifetime.(1) Nationally, a woman’s risk of hip fracture is equal to her combined risk of breast, uterine and ovarian cancer.(2) Individuals with fractures may experience pain, dependence, depression and skeletal deformity.(3) Only ~40% of hip fracture survivors are able to return to their prior level of activities of daily living (ADLs), and even fewer (~25%) return to their prefracture level for instrumental ADLs. Between ~15-25% of hip fracture patients will require institutionalization(1) and the one-year mortality rate is 12-36%.(4)(5) Up to 90-95% of fractures in hospitalized patients >60 years are attributable to osteoporosis.(6)(7) Currently <15% of those with fragility fractures are evaluated and treated for osteoporosis despite a 1.5-9.5-fold increased risk of future fracture.(6)(8)(9)

Although important steps have been initiated in advancing efforts to diagnose and treat osteoporosis and to reduce barriers that prevent diagnosis and treatment,(8)(10)(11)(12)(12) there remain many patients who are evaluated for bone loss for the first time with either advanced disease or at the time of fracture.(13)(14)(15)(16)

There are many barriers to initiating treatment for patients who have or are at risk for osteoporosis and fractures.(12) Lack of patient and primary physician knowledge, lack of awareness and use of current osteoporosis guidelines, and the perception by orthopaedic surgeons that evaluation and treatment of osteoporosis is not their responsibility may all pose difficult challenges. The cost of therapy, time and cost of diagnosing osteoporosis, side effects of medications, as well as confusion about medications or their effectiveness, may also account for failure to adequately treat patients with likely osteoporosis. Other potential barriers include complex medical conditions in elderly patients, reluctance of elderly patients to add more medications, lack of access to BMD testing and lack of time to address secondary prevention.

General Approach to Evaluating Patients With Osteoporosis and Osteoporotic Fractures

All patients with or at risk for osteoporosis should have a complete skeletal history, risk factor assessment, physical examination (including fall assessment), laboratory studies to rule out possible secondary causes of bone loss, and a measurement of bone mineral density (BMD). The approach to the patient with an osteoporotic fracture incorporates these same basic clinical principles, but with the added considerations that the majority of patients with fragility and vertebral compression fractures are not likely to get evaluated for underlying causes of bone loss and their evaluations should be conducted with the intention to reduce their high future morbidity and mortality as well as to preserve function.

Skeletal History

A complete skeletal history should include documentation of previous fracture – how they were sustained (traumatic versus minimal trauma) and if delayed fracture healing occurred. Multiple falls, even in the absence of previous fracture, should be carefully explored for potential mechanisms. Previous diagnosis of osteoporosis, time since initial diagnosis, and previous or current treatments should be obtained. Other information from the skeletal history should include known bone deformities, complaints of bone or musculoskeletal pain, reduced mobility, height loss and current primary bone disorders. Other details related to fracture risk is formally obtained by a risk factor assessment.

Risk Factor Assessment

The assessment of risk for bone loss and fractures can be divided into categories of personal risk factors, secondary medical conditions that cause bone loss and medications that adversely affect mineral metabolism and/or bone turnover.(17)(18)

Non-modifiable personal risk factors associated with osteoporosis include a family history of osteoporosis or fracture, low calorie intake or calcium/vitamin D deficient diet during formative years, personal history of fracture as an adult, increasing age, early menopause (<45 years old), late menarche (>16 years old), thin body frame, history of amenorrhea or irregular menstrual periods, female sex, white (and perhaps Asian) ancestry, history of prolonged periods of bed rest (or immobilization) and tallness.

As reflected by their inclusion in multiple algorithms that predict the need for bone mineral density (BMD) testing, age and body weight, as well as lifetime exposure to estrogen in women, are among the more important personal risk factors.(19)(20)(21)(22)(23)(24)

Osteoporosis and fractures are less common in men due to their larger skeletons, bone loss starting later in life, slower progression, and the absence of a rapid phase of bone loss as occurs in menopause; however, men have much higher mortality and chronic disability rates after a hip fracture.(25) They are also more likely to have a secondary cause of bone loss compared to women.

Potentially modifiable personal risk factors associated with osteoporosis and/or fracture are low body weight, low calorie intake or calcium/vitamin D deficient diet, sedentary lifestyle or inadequate physical activity, heavy alcohol use (three or more drinks/day), high salt intake, tobacco cigarette smoking (active or passive) and high caffeine intake.(17)(18) Independent risk factors for fractures include impaired neuromuscular function, decreased visual acuity, sedative/hypnotic drug use, and frequent falls, previous fractures and low body weight.

Secondary Medical Conditions

As outlined in Table 1, a number of co-existing or past medical conditions can predispose individuals to continued bone loss.(26) Elderly patients are unlikely to present with genetic conditions that otherwise would present much earlier in life or limit life expectancy. However, there are predisposing medical conditions that are more likely to contribute to age-related bone loss and fracture such as vitamin D deficiency, post-menopausal status and chronic kidney disease.

Medications that Adversely Affect Mineral Homeostasis or Bone Turnover

Bone loss due to medications is common,(27)(28) especially in the elderly. However, evidence that supports a clear etiological role for certain medications is variable. A list of medications with well-established contributions to bone loss is shown in Table 2. Glucocorticoid-induced osteoporosis(29) and bone loss due to immunosuppressive therapy after solid organ transplant(30) remain challenging problems.

Why Is Risk Factor Assessment Important?

Most fractures related to osteoporosis occur in individuals whose BMD measurements are not consistent with osteoporosis, so combining risk factors with BMD increases the likelihood of predicting the risk of fracture. Low bone density is a strong predictor of fracture risk, but it still does not carry the same weight as other risk factors or combination of risk factors.

A recent Web-based tool called FRAX (http://www.shef.ac.uk/FRAX/tool) uses BMD and a combination of risk factors to predict the likelihood of fractures (10-year risk of a major fracture or hip fracture), but may have limited value in clinical practice.

Risk factors used in the FRAX algorithm include prior fracture, age, BMI (without BMD), femoral neck BMD, family history of hip fracture (parents), corticosteroid use, alcohol intake (>2 drinks/day), smoking (current), rheumatoid arthritis and secondary osteoporosis. The use of FRAX in clinical practice can provide supportive data for decision-making about pharmacological interventions when the decision to treat is in doubt. It is applicable to postmenopausal women and men >50 years old of all racial backgrounds but most appropriate for otherwise healthy patients with stable skeletal status. The National Osteoporosis Foundation (NOF) has promoted the guideline that treatment should be initiated in patients with osteopenia (T-score by DXA between -1 and -2.5) and a 10-year risk of major fracture >20% (or of hip fracture >3%) as calculated by FRAX.

Use of the FRAX algorithm is limited by the paucity of information on treatment efficacy in non-osteoporotic patients, the lack of accounting for BMD at sites other than femoral neck and the failure to consider risk factors for falls. FRAX also defines some risk factors as categorical rather than continuous (e.g., glucocorticoid use), and so makes no distinction between high- or low-dose steroid use (or duration of use).

FRAX is not applicable to young adults, patients on treatment, when rapid bone loss is expected (early menopause, discontinuation of HRT, hormone deprivation therapy, initiation of glucocorticoids) or secondary causes of bone loss. Caucasian fracture rates are based on a small number of patients and non-Caucasian fracture rates extrapolated from Caucasian rates. Some of these pitfalls are likely to be addressed with future versions of FRAX.

Osteoporosis In Men

Osteoporosis and fractures are less common in men because of their larger skeletons, bone loss starting later in life, slower progression and the absence of a rapid phase of bone loss as occurs in menopause. Men suffer one-fifth to one-third of all hip fractures, and half as many symptomatic vertebral fractures compared to women; however, men have much higher mortality and chronic disability rates after a hip fracture.(25) They are also more likely to have secondary cause(s) of bone loss compared to women.

Physical Exam

The physical examination should focus on detecting the consequences of osteoporosis (fractures), secondary medical causes of bone loss and an initial assessment of fall risk. In the absence of exam findings for vertebral compression fractures or occult nonvertebral fractures, physical signs cannot confirm the diagnosis of osteoporosis. Findings that support occurrence of vertebral fractures include hyperkyphosis (where strict upright posture becomes impossible).(31) This is accompanied by height loss, and with multiple vertebral fractures, narrowed gapping between the ribs and ilium with or without the 12^th rib resting on the iliac crest (rib-on-pelvis syndrome). Other suggestive findings may include a protruding abdomen, paravertebral muscle spasm and vertebral tenderness. Hyperkyphosis may be measured by a flexicurve device, Cobb angle calculated from a standing lateral radiograph (>50°), wall-occiput test (wall-occiput distance >0 cm), or rib-pelvis test (rib-pelvis distance ≤2 finger breadths).(31)(32)

Vertebral fractures, however, account for only one cause of hyperkyphosis. Other possibilities include muscle weakness, disk height loss, ligament contraction, physical inactivity, postural changes and heritability. The possible consequences of hyperkyphosis, regardless of etiology, are compromised pulmonary function, poor physical function, falls, osteoporosis fractures, decreased quality of life, depression and increased mortality independent of vertebral fractures.(32)(33) Occult nonvertebral fractures may present with bony tenderness, difficulty with weight bearing, as well as difficulty with joint positioning or movement.

The abundance of medical disorders that can cause bone loss precludes a complete description of exam findings for each condition. Examples of obvious signs to prompt further inquiry include the bony deformities consistent with rheumatoid arthritis, stigmata of chronic alcoholism and liver disease, scars suggesting neck surgery (thyroid or parathyroid) and skin changes associated with specific endocrinopathies.

A minimal fall assessment on physical exam should include the ability to rise from a chair without using the upper extremities, measurement of resting pulse, gross visual testing, walking facility and heel-to-toe ambulation. Difficulty in rising from a chair without the use of the arms, a resting pulse >80, poor visual acuity and gait dysfunction, including imbalance, all suggest increased fall risk.

Laboratory Testing

Screening laboratory tests serve to rule out secondary medical causes of bone loss. Normal serum electrolytes, liver and kidney function tests, albumin, total protein, calcium, intact parathyroid hormone (PTH), 25-hydroxy vitamin D, phosphorus, magnesium, thyroid-stimulating hormone (TSH), serum testosterone (in men) and a complete blood count eliminate most secondary causes of bone loss. A 24-hour collection for urinary calcium, sodium and creatinine may also be helpful. A low 24-hour urinary calcium suggests vitamin D deficiency, osteomalacia or malnutrition (e.g., celiac sprue). High urinary calcium suggests renal tubular calcium leak, absorptive hypercalciuria, high sodium diet, or excessive bone resorption due to malignancy, hyperparathyroidism, hyperthyroidism or Paget's disease.

In women without a history of diseases or medications known to adversely affect the skeleton, 32% had disorders of calcium metabolism (hypercalciuria, malabsorption, hyperparathyroidism, vitamin D deficiency).(34) Measurement of 24-hour urine calcium, serum calcium, PTH and TSH (in those on thyroid replacement) would have been sufficient to diagnose 85% of underlying causes in this group.(34) In another study, except for measurement of TSH, routine laboratory tests were not found to be useful.(35) More specialized tests should also be considered based on clinical suspicion, including serum and urine protein electrophoresis, and a 24-hour urinary free cortisol or overnight dexamethasone suppression test.

Markers of bone turnover including various collagen breakdown products may serve to distinguish between high and low turnover bone loss. Serum and urine markers are discussed in detail below under "Monitoring osteoporosis therapy."

Bone Mineral Density (BMD) Testing

Dual-energy x-ray absorbtiometry (DXA) is currently the gold standard for measurement of BMD. However, measurement of BMD is not necessary to make the diagnosis of osteoporosis after a fragility fracture. Current T-scores (expressed as the number of standard deviations above or below the normal BMD of young adults) are useful to establish a baseline for purposes of monitoring treatment efficacy and should be performed. Very low Z-scores (expressed as the number of standard deviations above or below the normal BMD for the same aged individuals) may indicate either the failure to obtain adequate peak bone mass during an individual’s formative years, or the presence of secondary cause(s) that have contributed to bone loss. In general, the risk of osteoporotic fracture doubles for every drop of one standard deviation in T-score.(36)(37)

DXA and similar radiographic techniques only provide information about BMD. MRI-based bone imaging holds future promise for construction of 3-D volumes, akin to virtual bone biopsies, which can be sampled repeatedly in time and in the identical location.

Indications for BMD testing vary among guidelines but those suggested by the National Osteoporosis Foundation (NOF) include, age >65, patients with history of fractures, estrogen-deficient women, hypogonadal men, persons taking long-term corticosteroids, persons with endocrinopathy, persons with significant risk factors regardless of age, assessment of treatment efficacy and persons considering therapy for osteoporosis when BMD will facilitate treatment decisions.(38)(39)

Indications for vertebral fracture assessment (VFA)(40) include two or more of the following: advanced age, self-reported prior non-vertebral fracture, historical height loss of >3 cm (1.2 in), chronic systemic diseases associated with increased risk of vertebral fractures (e.g., COPD, seropositive rheumatoid arthritis, Crohn’s disease) and current androgen deprivation or orchiectomy. VFA may also be performed in individuals with known osteopenia and advanced age, historical height loss >6 cm (2.4 in) or prospective height loss >3 cm (1.2 in), or self-reported vertebral fracture not previously documented. VFA is also useful to evaluate patients with current chronic glucocorticoid therapy or osteoporosis, if documentation of vertebral fracture(s) will alter management.

Treatments and Prevention

Treatment of osteoporosis and fragility fractures requires a multi-pronged approach: changing modifiable personal risk factors, management of secondary medical causes of bone loss, reduction or elimination of medications that adversely affect mineral homeostasis and bone turnover, improving fall and injury risk, and initiating pharmacological and non-pharmacological interventions that increase bone mass and improve skeletal structural fidelity. Prevention of subsequent fractures requires the early identification and evaluation of patients who sustain an initial fragility fracture, adequate treatment and monitoring of osteoporosis, as well as environmental and activity modifications that address the circumstances of the presenting fracture. The antifracture efficacy of the most frequently used treatments for osteoporosis(41)(42) is shown in Table 3.

Clinical Pathways in the Care of Fragility Fracture

Recent studies have shown that dedicated interdisciplinary collaboration among orthopaedic surgeons, medical specialists in metabolic bone disease, screening coordinators, nurse-educators and information technologists can play important roles in improving osteoporosis care and therefore potentially help decrease the risk of subsequent fragility fractures.(10)(11)(12)(43)(44)(45) Even if barriers to adequate evaluation and treatment are overcome, the clinical challenge still remains that a proportion of patients, including those followed by dedicated interdisciplinary teams, refracture despite being placed on osteoporosis treatment after their incident fracture.(15) Patients who are likely to refracture are older, are more likely to sustain another hip fracture after an incident hip fracture and are likely to refracture early, particularly when the incident fracture is of the hip; they are often already on treatment for osteoporosis.

Calcium, Vitamin D and Nutritional Considerations

Clinical trials that evaluated many of the currently available osteoporosis therapies included calcium and vitamin D supplementation in both the treatment and control groups, and thus require that patients who receive these therapies are calcium- and vitamin D-replete to achieve the same or similar efficacies as study subjects.

There is a decline in calcium absorption with age, due at least in part to vitamin D insufficiency or deficiency. Insufficiency of vitamin D is a frequent finding among community-dwelling elderly and practically ubiquitous in institutionalized elderly.(46) Risk factors for vitamin D depletion in the elderly include deprivation of sunlight, poor nutrition, age-related changes in skin and renal function, darker pigmentation, living at higher latitudes, home-bound status, institutionalized status and previous hip fractures. There is a positive correlation between 25(OH) vitamin D levels and bone mineral density, with the risk of fractures increased at values <30ng/ml.(47)

Calcium supplementation alone slightly lowers the risk of vertebral but not nonvertebral fractures.(48) Calcium alone does not lower fracture risk in patients with prior fracture, even after about four years of supplementation.(49) However, supplemental vitamin D appears to reduce fracture risk when taken in doses sufficient to keep serum 25(OH) vitamin D levels above about 32.5 ng/ml. In trials where 25(OH) vitamin D levels were measured, fracture risk reduction tended to be inversely proportional to circulating levels.(50) Fracture risk reduction is thought to be related to the effects of vitamin D on both muscle and bone.

Dietary protein is an important factor for continued bone health. Age-related bone loss is inversely related to protein consumption,(51) an effect that is associated with adequate calcium and vitamin D intake.(52) Although high protein consumption had been considered potentially detrimental to bone as a result of increases in urinary calcium, this appears not to have an effect on bone turnover.(53) Protein intake of about 1 g/kg body weight/day improves patient outcomes post-hip fracture, and serum albumin levels are a very reliable predictor of survival after fracture.(54)(55)(56) Thus adequate dietary protein intake and protein supplementation, with the possible exceptions of those with chronic kidney disease or history of nephrolithiasis, should be prescribed for patients with osteoporosis and previous fracture.

Similar concerns have been raised about the effects of excessive intake of sodium, caffeine, phosphorus and sugar causing increased urinary calcium losses and altered calcium homeostasis that contribute to bone loss. Although urinary calcium losses are usually followed by reduced renal calcium clearance,(57)(58) this may not be efficiently accomplished in the elderly. Further, the beverage sources for caffeine, phosphorus and sugar usually qualify as being of low nutrient density (LND) and, as such, their consumption is often a poor substitute for more calcium- and protein-rich drinks.

Replacement of vitamin D in patients with chronic kidney disease (CKD) should be performed when the 25-hydroxy vitamin D levels are low and target range of intact plasma PTH for that CKD stage is exceeded. Inactive forms for vitamin D such as ergocalciferol are suggested for replacement. Active vitamin D therapy is used in patients with stage 3 and 4 CKD where the serum levels of 25-hydroxy vitamin D are >30ng/ml (75 nmol/L) and intact PTH above the target range. These recommendations are based on the K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease (http://www.kidney.org/professionals/kdoqi/guidelines_bone/index.htm).

Bisphosphonates

The primary mechanism of action of bisphosphonates is the reduction of osteoclastic bone resorption. Potential differences among bisphosphonates are their relative affinity for bone and their antiresorptive capacity. These differences may translate into clinical consequences such as speeds of onset and duration of effect, relative reduction in bone turnover, uptake in cortical and trabecular bone, and anti-fracture effects (e.g., vertebral vs. nonvertebral). However, except for anti-fracture effects and side effect profiles based on route of administration, there are currently no clear differences.

Persistence of oral bisphosphonate therapy is a problem.(59)(60)(61)(62)(63)(64) Only about 50% of patients are adherent to their regimen after one year. Determinants of non-adherence include younger age, comorbidities, health plan and prescription costs. Reasons for discontinuation of treatment are side effects, poor understanding of benefits, inconvenience and use of multiple medications. Compliance tends to decline over time. Possible solutions include the prescription of weekly or monthly oral formulations, use of IV formulations to assure compliance and to eliminate GI side effects of oral forms, patient education (regarding osteoporosis, treatment options and benefits of compliance) and patient monitoring.

Oral forms are taken in the morning 30-60 minutes before eating, and with a full glass of water. Upright position should be maintained for at least 30-60 minutes to avoid prolonged contact with the gastrointestinal (GI) mucosa. Bisphosphonates are not recommended in patients with creatinine clearance of less than 30-35mL/min. Potential short-term complications of bisphosphonate use are GI intolerance (heartburn, esophageal irritation, esophagitis, abdominal pain, diarrhea), severe bone, joint and/or muscle pain, ocular inflammation (abnormal or blurred vision, ocular pain, conjunctivitis, uveitis, scleritis) and acute-phase reactions (fever, myalgias, flu-like syndrome).(65)(66)(67) Potential long-term complications include osteonecrosis of the jaw, subtrochanteric and femoral shaft fractures and esophageal cancer.

Osteonecrosis of the jaw (ONJ) results in an area of exposed bone in the maxillofacial region in which there is no healing over eights weeks from the time of discovery. Usual precipitating events include recent tooth extraction or oral surgical procedure, abrasion in trauma-prone location (e.g., mylohyoid ridge in edentulous patients, tori), and chronic severe periodonitis or other smoldering infection. ONJ may be symptomatic or asymptomatic. It may be infected or non-infected. The incidence of ONJ can be as high as 7% in patients treated with IV bisphosphonates for myeloma or breast cancer, but only 1/100,000 to 1/250,000 treatment-years in patients treated with oral bisphosphonates for osteoporosis. In acknowledgement of the of the very low incidence of ONJ when bisphosphonates are used to treat osteoporosis, a 2009 position statement by the American Association of Oral Maxillofacial Surgery concluded: "The current level of evidence does not support a cause and effect relationship between bisphosphonate exposure and osteonecrosis of the jaw."(68)

The link between bisphosphonate use and atypical subtrochanteric and femoral shaft fractures is weak.(69) The incidence of such fractures appears to be very low in comparison with the number of prevented fractures and a causal association has not been established. Recent observations, however, suggest that the risk of atypical fractures increases with the duration of bisphosphonate exposure. The relationship between esophageal cancer and bisphosphonate use is also unclear.

Carefully chosen and monitored, the side effects of bisphosphonates can be minimized. Gastrointestinal upset due to esophageal irritation is probably the most common complaint with use of oral bisphosphonates. This side effect can be ameliorated by following proper instructions for administration by mouth and by increasing the dosing interval.

Estrogens and Selective Estrogen Receptor Modulators (SERMs)

Estrogen replacement in postmenopausal women, with or without a progestin, reduces vertebral and nonvertebral fractures. The use of hormone and estrogen therapy for this purpose, however, has been limited as a consequence of adverse outcomes reported in the Women’s Health Initiative (WHI) study.(70)(71)(72) Therapy with estrogen plus progesterone was associated with an increased risk of deep venous thrombosis (DVT), pulmonary embolism (PE), stroke, myocardial infarction and breast cancer. Estrogen therapy alone was associated with an increase in the risk of DVT, PE and stroke.

Although current guidelines suggest that hormone replacement be used primarily for treatment of menopausal symptoms and for the shortest period of time necessitated for symptom relief, the role of estrogen alone or in combination with a progestin is still far from being adequately explored. In specific populations, such as early postmenopausal women, and under specific regimens, such as low-dose estrogen or forms other than conjugated equine estrogens, the risk benefit ratios for the use of hormones may be different from that seen in the WHI study. Estrogen replacement may currently be considered for osteoporosis treatment after all other alternatives have been exhausted, and when all risks and benefits are fully discussed with the patient.

Selective Estrogen Receptor Modulators (SERMs), such as raloxifene, increase BMD at the spine and hip but only reduce the incidence of vertebral fractures and not hip or other nonvertebral fractures.(73)(74) Among the adverse events that are associated with both estrogen and tamoxifen – including DVT, gallbladder disease, endometrial cancer and cataracts – raloxifene is associated with a higher relative risk for DVT but not other adverse events.(75) Raloxifene may be considered for use in combination with other medications in selected women with or at risk for vertebral fractures.

Teriparatide

Teriparatide or PTH(1-34) is the only FDA-approved anabolic agent for bone loss and it confers a reduction of vertebral and nonvertebral fractures in high-risk individuals.(76)(77)(78)(79) Studies on combination or sequential therapy in previously untreated women and men, where PTH analogues were combined with or followed alendronate treatment, have produced results suggesting no clear benefit to either permutation.(77)(80)(81) Prior long-term alendronate treatment might diminish, but does not eliminate, increases in BMD with use of PTH analogues.(82)(83) It is likely that BMD is lost in individuals who do not take antiresorptive agents after cessation of PTH analogues, and that antiresorptive therapy can maintain or further increase PTH-induced gains.(81)(84)(85)(86)(87)(89)

All PTH analogues should be avoided in those with an elevated risk for osteosarcoma, including individuals with a history of Paget’s disease, irradiation or unexplained elevations in alkaline phosphatase. Other contraindications include metastatic bone cancer, multiple myeloma, hyperparathyroidism and hypercalcemia. Treatment with teriparatide is limited to a two-year course because of concerns over the possibility of osteosarcoma; however, no substantiated case of osteosarcoma has been reported to date.(90)(91)

The recommended dose of teriparatide is 20 mcg once a day, administered as a subcutaneous injection into the thigh or abdominal wall. It should be administered initially under circumstances in which the patient can sit or lie down if symptoms of orthostatic hypotension occur.

Denosumab

Denosumab has recently been approved for the treatment of postmenopausal women with osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, denosumab reduces the incidence of vertebral, non-vertebral and hip fractures.(92) Denosumab functions to decrease osteoclastogenesis. Experience with denosumab in clinical practice is limited but it may be used in place of bisphosphonate therapy or as an alternative in patients who cannot tolerate bisphosphonates.

Physical Activity and Exercise

Physical activity is a critically important strategy to reduce osteoporosis and fractures in the elderly. It is well established that increases in BMD or reductions in bone loss occur with sufficient exercise or mechanical loading.(93)(94) Physical activity and exercise at virtually any age can still increase BMD and potentially reduce fracture risk with minimal therapeutic harm.(94)(95)(96)

Studies in humans and animals suggest that physical activity and exercise strategies allow adequate rest periods between skeletal loads, limit loading cycles to avoid bone desensitization and incorporate low-level strain protocols to maximize bone formation.(97)(98)(99) Physical rehabilitation after fracture aims to increase strength and mobility to reduce falls, maintain or build BMD and, in the case of vertebral fracture, decrease kyphotic posture.(100) Newer physical modalities such as whole body vibration may offer future prospects of non-pharmacologic treatment regimens for fracture prevention.(101)

Prolonged bed rest or severely reduced physical activity cause devastating atrophy of trabecular and cortical bone, as well as declines in numerous body systems. BMD may decline as much as 1-2% per week in both weight-bearing and nonweight-bearing bones, with little or unpredictable recoup after re-initiation of ambulation.(102)(103)(104) To the extent possible, bed rest and reduced physical activity should therefore be minimized in patients with a prior history of fracture.

The prescription for physical therapy should include weight-bearing and resistance exercise, back-strengthening and postural training, balance training (or Tai Chi), and stretching for tight soft tissues and joints. Strenuous or sudden twisting, turning or flexion, especially when lifting or carrying an object, should be avoided.

Rehabilitation in patients able to do only limited physical therapy is a challenge. Partial bed rest (when necessary) should be substituted for extended immobilization, and for the shortest periods of time. Instruction on the safe performance of activities of daily living (ADLs) and movements (transfers, lifting, walking) should be given. Assistive devices for ambulation and for reaching/lifting to compensate for deficits should be recommended. Long-term bracing should be avoided to minimize muscle weakness (e.g., trunk orthoses for pain relief after vertebral fracture).

Monitoring Osteoporosis Therapy

Osteoporosis therapy is generally monitored by regular measurements of BMD since there is a relationship between increased BMD from antiresorptive therapy and decreased fracture risk. However, increased BMD and decreased fracture risk are not the same for the spine versus non-spine fractures. For example, there are small reductions in the risk of fracture at the spine even without increases in BMD, but not at non-spine locations. In general, reductions in fracture risk with antiresorptive agents are greater than expected from increases in BMD and are not proportional to increases in BMD. Suggested intervals for monitoring by DXA are based on the observed BMD rates of change with currently available antiresorptive agents and the reproducibility of DXA BMD testing (Table 4). Changes in BMD >3% are considered real biologic changes but are usually not reached in the spine before one year or in the hip before two years of treatment.

Monitoring osteoporosis therapy is sometimes also performed by measurement of bone turnover markers.(105) Serum markers of bone formation are made by osteoblasts (e.g., bone alkaline phosphatase, osteocalcin, C- and N-terminal propeptides of type I collagen). Urine bone resorption markers are breakdown products of type I collagen (pyridinoline [PYR], deoxypyridinoline crosslinks [D-PYR], C- and N-telopeptides of type I collagen [CTx, NTx]).

These markers serve as a dynamic reflection of bone remodeling rates. They do not, however, provide information on existing BMD and cannot confirm the absence or presence of osteoporosis. They are not a substitute for BMD testing but can help to support the diagnosis of high turnover bone loss (e.g., hyperparathyroidism, rheumatoid arthritis). Suppression of bone turnover occurs far more rapidly than detectable changes in BMD and markers reach a nadir within 3-6 months of therapy initiation. The imprecision of measuring markers is far greater than measuring BMD, and cutoff values for the use of markers are uncertain. Desirable levels are considered to be in the premenopausal range, usually at least 20-50% of baseline.

Prevention

Since osteoporosis increases the risk of fracture from both low- and high-impact trauma, evaluation should be pursued in both settings.(106) The initial evaluation includes referral of the patient to an osteoporosis specialist, which can be as part of a fragility fracture pathway, as part of a targeted outreach program to primary care physicians,(107) or as inpatient or outpatient direct consultations to endocrinologists, rheumatologists, geriatricians or other specialists with training in bone disorders. In-hospital medical management aimed at prevention should also include adequate pain control without NSAID use, nutritional evaluation with recommendations for adequate protein intake and initiation of physical rehabilitation.

Prevention strategies in the outpatient setting should incorporate pharmacologic treatment with antiresorptive or anabolic agents, optimal calcium and vitamin D intake, treatment of secondary medical causes of bone loss, approaches to reduce modifiable risk factors, and physical rehabilitation that includes a fall assessment and prescribed exercise for strength, balance and mobility. Weight-bearing and other exercises should be tailored to the individual. Education, environmental modifications and specific aids should also be prescribed, ideally by a multidisciplinary team. Hip protectors may not be an ideal physical aid to prevent future fracture since long-term adherence is a problem; further, some data suggest that they are clearly ineffective in some populations.(107)(108) Patient adherence to pharmacologic therapy, exercise and dietary regimens, as well as environmental and safety concerns, should be regularly monitored.