1.
Inadequate sun exposure
2.
Low calcium intake
3.
Inadequate physical activity
4.
Immobilization
5.
Frequent falling
6.
Smoking (active or passive)
7.
Alcohol abuse
8.
Anorexia nervosa
FRAX, a computer-driven tool easily accessible on the Internet (http://www.shef.ac.uk/FRAX), can help guide physicians with the use of DXA data (when available) along with significant contributors to osteoporotic fracture to assess fracture risk. The FRAX algorithms request a response to 12 questions (BMD at the femoral neck, age, sex, weight, height, previous fracture history, current cigarette smoking, glucocorticoid use, history of rheumatoid arthritis, secondary causes for osteoporosis, alcohol use, and parental history of hip fracture) and calculate a 10-year probability of fracture of the hip and of major osteoporotic fracture (clinical spine, forearm, hip, or shoulder fracture); this information can then help guide decisions regarding timing of treatment initiation and therapeutic choices [21]. The FRAX has been used as a guide to help clinicians in deciding whether intervention therapy with an osteoporotic medication such as an antiresorptive agent is warranted. The current NOF guidelines recommend treating patients with low bone mass and FRAX 10-year risk scores of ≥3 % for hip fracture or ≥20 % for a major osteoporotic fracture, to reduce their fracture risk. Notably, additional risk factors such as frequent falls that are not represented in FRAX warrant individualized clinical judgment.
A patient with a normal BMD does not need to have repeat BMD assessment for at least 5 years, unless there is a change in the clinical picture, when earlier evaluation may be considered. Because of the limitations in the precision of testing, a minimum of 2 years is usually recommended to reliably measure a change in bone density. However, there are some circumstances where a yearly BMD assessment may be of value especially in patients who are on medications that can cause rapid bone loss including glucocorticoids and several antiestrogen medications used in the treatment of breast cancer [19].
Clinicians can be confused when they receive a DXA report that suggests a normal BMD in the lumbar spine and osteoporosis in the hip. There can be several explanations for this dichotomy. The most common reason for a big site discrepancy in BMD results is due to artifacts in the lumbosacral spine including osteoarthritis, osteophytes, and compression fractures which will falsely increase BMD at the lumbar spine, thus yielding a higher T score. Interpretation of BMD status from a DXA report is based on whatever skeletal site has the lowest T score.
Risk Factors and Prevalence
It is estimated that 43.1 million Americans have low bone mass and another 9.9 million are currently affected by osteoporosis, and further increases in prevalence are expected by 2020 [18, 19]. There are a variety of risk factors for the development of low bone mass and osteoporosis (Tables 8.1 and 8.2). Major risk factors include low BMI (<20), Caucasian extraction, nulliparity, early menopause, positive family history, low physical activity or prolonged immobilization, cigarette smoking, alcohol abuse, anorexia, low calcium intake, chronic vitamin D deficiency, and some medications (Table 8.2) [1, 2, 21–24]. We also found that with premature hair graying, i.e., that if 50 % of the hair turned gray by the age of 40, both men and women had a fourfold increased risk for having low bone mass/osteoporosis [3]. There are a wide variety of additional acquired and inherited causes for low bone mass/osteoporosis as listed in Table 8.2. Some of the major inherited causes of skeletal fragility relate to mutations in genes that are responsible for the production of the collagen-elastin matrix in the skeleton including osteogenesis imperfecta, Ehlers-Danlos syndrome, and Marfan syndrome [1, 2]. The major acquired secondary causes are associated with endocrine disorders including hyperparathyroidism, hyperthyroidism, hypercortisolism, and hypogonadism and a variety of medications, most notably glucocorticoids [19, 21–26] (Table 8.2).
Table 8.2
The more common secondary causes of low bone mass and osteoporosis
Non-medication-related causes | Medication-related causes |
Vitamin D deficiency | Glucocorticoids (>5 mg/d prednisone or equivalent for ≥3 months) |
Hyperparathyroidism | Aromatase inhibitors |
Hyperthyroidism | Depo-medroxyprogesterone (premenopausal contraception) |
Diabetes mellitus (type I and II) | GnRH (gonadotropin-releasing hormone) agonists |
Premature menopause (<40 year) | Anticonvulsants |
Cushing’s syndrome | Anticoagulants (heparin) |
Hyperprolactinemia | Proton pump inhibitors |
Androgen insensitivity | Selective serotonin reuptake inhibitors |
Athletic amenorrhea | Tamoxifen® (premenopausal use) |
Intestinal malabsorption disorders | Cancer chemotherapy |
Primary biliary cirrhosis | Major genetic causes |
Multiple myeloma | Osteoporosis imperfecta |
Multiple sclerosis | Ehlers-Danlos syndrome |
Spinal cord injury | Marfan syndrome |
End-stage renal disease | |
Hypercalciuria |
Clinical and Laboratory Evaluation
Physical examination should include documentation of accurate baseline height, preferably with a stadiometer, for later comparisons to rule out silent spinal fractures where loss of height may be the only overt sign. An increase in skin elasticity or evidence for a “doughy textured” skin and increased flexibility of joints may be evidence for the genetic disorder Ehlers-Danlos/hypermobility syndrome which has been associated with fragility fractures [1, 2]. Other red flag indicators of possible low bone mass include a dowager’s hump (raising suspicion for underlying vertebral fracture/s), exophthalmos (suggesting hyperthyroidism as a mechanism for bone loss), blue sclerae (raising concerns for an underlying collagen disorder), centripetal obesity and proximal muscle wasting (hallmarks of cortisol excess), and a history of prolonged immobility. Palpation with thumb or forefinger on the upper portion of the sternum pushing with a reasonable amount of force may help in the diagnosis of vitamin D deficiency osteomalacia especially if the patient is exquisitely sensitive to the maneuver; this is often misdiagnosed as a trigger point for fibromyalgia [4].
Blood tests should include serum total calcium, albumin, phosphorus, alkaline phosphatase, liver function tests, creatinine, and thyroid-stimulating hormone (TSH). Osteocalcin the major non-collagenous protein in the skeleton and procollagen-type 1 N-terminal propeptide are serum markers for osteoblast activity similar to bone-specific alkaline phosphatase. Urine N-telopeptide and serum C-telopeptide are markers of osteoclast activity and bone resorption. These markers are typically used in clinical trials to evaluate the medication effect on bone formation and bone resorption of activity. However, the clinical utility of measuring these bone biomarkers for individual patient care is not well established and as a result is often not covered by health insurance [10].
Neither the Institute of Medicine (IOM) nor the Endocrine Society recommends routine screening for vitamin D deficiency (serum 25-hydroxyvitamin D [25(OH)D]) particularly if women are of normal weight, taking adequate supplements, and not on medications that influence vitamin D metabolism [27]. For women and men with low bone mass or osteoporosis, there is no need to screen for vitamin D deficiency. Instead the recommendation is to evaluate them for their vitamin D intake, and if less than 2000 IUs of vitamin D a day, the recommendation is to supplement following Endocrine Society’s Guidelines of 1500–2000 IUs daily. An alternative effective method is to provide the patient with 50,000 IUs of vitamin D once every 2 weeks. This is both safe and effective [5, 6]. However, screening and monitoring vitamin D status with a serum 25(OH)D level is recommended in women with malabsorption syndromes, including Crohn’s disease, ulcerative colitis, and gastric bypass surgery, and in those on glucocorticoids, antiseizure medications, and HIV medications. In addition, the Endocrine Society’s Vitamin D Practice Guidelines recommends monitoring vitamin D status in obese women and in those who have a hypersensitivity to vitamin D including Williams syndrome and chronic granulomatous disorders including sarcoidosis and tuberculosis among others [27].
Strategies to Prevent Low Bone Mass and Osteoporosis
Calcium Intake
Adequate calcium and vitamin D throughout life helps to maximize a person’s genetically programmed BMD and maintain bone health [27–29]. A low intake of calcium during the formative teenage and young adult years results in a decrease in attainable peak bone mass, which occurs between the ages of 20–30 years. Young adults can lose about 0.25–0.5 % of their bone mass yearly if they are not obtaining an adequate amount of calcium and vitamin D [2]. This unrelenting loss in BMD over several decades can lead to a significant 5–15 % reduction in BMD before the age of 50. After reaching peak bone mass, young adults need to continue taking the recommended daily intake of 1000 mg of calcium from dietary sources and or supplements. Eight ounces of dairy such as skim milk or yogurt provides 300 mg of calcium and is an excellent source of whey proteins and essential amino acids which are important for bone health as well. Given the prevalence of protein deficiency among older women, this author encourages them to consume dairy products not just for calcium but also for the protein content. For those who are lactose intolerant or prefer not to ingest dairy products, soymilk and almond milk are fortified with calcium carbonate. Some commercial orange juices are also fortified with calcium citrate/malate in an amount comparable to milk. Thus ingesting three servings of dairy or calcium-fortified orange juice satisfies the recommended daily allowance (RDA) for calcium for most young adults. For postmenopausal women, they are recommended to ingest at least 1200 mg of calcium daily (through a combination of diet and supplements) [27–31]. However, since dietary sources of calcium are highly desirable even for postmenopausal women 50 years and older, this author recommends three servings of milk or other calcium-containing products without additional calcium supplementation. There is no evidence that increasing calcium intake above the RDA will have any additional benefit on BMD. In fact higher calcium intakes above the recommended RDA increase the risk for kidney stones, cardiovascular calcifications, and stroke [27, 32, 33]. Although there are concerns that women with achlorhydria or iatrogenic achlorhydria due to proton pump inhibitor use may not efficiently absorb calcium carbonate, this limitation may be overcome by ingesting the supplement with food. Also for most kidney stone patients who are likely hyperabsorbers of oxalate, calcium citrate supplements may be a better choice than calcium carbonate [2].
Vitamin D Intake
Vitamin D deficiency can be very subtle and insidious with no obvious clinical manifestations other than nonspecific aches and pains in bones and muscles. Vitamin D-deficient women are often misdiagnosed as having fibromyalgia and chronic fatigue syndrome or are simply dismissed as being depressed [4]. Vitamin D deficiency causes low bone mass and osteoporosis by two mechanisms. Vitamin D deficiency results in a transient decrease in ionized calcium which is recognized by the calcium sensor in the parathyroid glands resulting in an increase in the production of parathyroid hormone (PTH). PTH helps conserve calcium by increasing tubular reabsorption of calcium in the kidneys. It also stimulates the kidneys to produce 1,25-dihydroxyvitamin D [1,25(OH)2D]. Since this hormone circulates at a concentration which is several orders of magnitude below that of 25(OH)D, the blood concentration of this hormone is usually normal or even elevated in a patient who was vitamin D deficient and therefore of no value in determining a person’s vitamin D status. A higher PTH level in vitamin D-deficient women also increases the number of osteoclasts in the skeleton which release HCl and collagenases destroying the matrix and releasing calcium into the circulation. In addition, high PTH activity also causes phosphaturia and hypophosphatemia which if sustained can result in an inadequate calcium phosphate product and lead to a mineralization defect known as osteomalacia. Whereas osteoporosis or low bone mass does not cause bone pain, osteomalacia causes aches and pains in the bones and muscles [4]. It is also worth noting that you cannot distinguish low bone mass, osteoporosis, and osteomalacia either by X-ray or bone densitometry [2]
As to how much vitamin D is required to be vitamin D sufficient depends on the circumstances. The IOM assumes that a majority of the population is vitamin D sufficient, i.e., 25(OH)D >20 ng/mL, and therefore recommended a daily intake of 600 international units (IUs) for all children over the age of 1 and for all adults up to the age of 70. The recommendation for adults over the age of 70 is 800 IUs daily [28]. The Endocrine Society concluded that to maximize bone health, a serum 25(OH)D >30 ng/mL should be maintained and a blood level up to 100 ng/mL was considered to be safe [27]. They therefore recommended higher doses (600–1000 IUs daily for children and 1500–2000 IUs daily for adults). For children and adults who are obese, with a body mass index (BMI) >30, a two- to threefold higher dose of vitamin D supplements is required [27]. With that being said, vitamin D deficiency, i.e., 25(OH)D < 20 ng/mL, remains common in all age groups and especially in postmenopausal women [27, 41, 42]. A simple but effective strategy to treat vitamin D deficiencies is to give 50,000 IUs of vitamin D2 once a week for 8 weeks to fill the “empty vitamin D tank.” The reason for vitamin D2 is that it is the only pharmaceutical form of vitamin D available in United States since it predated the FDA. Vitamin D3 has never been approved as a pharmaceutical. Supplement manufacturers have provided pharmacies with 50,000 IUs of vitamin D3 that can be prescribed by providers. We reported that this strategy is effective regardless of whether baseline 25(OH)D is undetectable or just mildly deficient [6]. In those who are severely deficient, blood levels of 25(OH)D rise rapidly to about 20 ng/mL. However, to achieve and maintain optimal vitamin D sufficiency, i.e., a 25(OH)D level of at least 30 ng/mL and preferably in the range of 40–60 ng/mL, as recommended by the Endocrine Society’s Practice Guidelines, continued supplementation is required after the initial 8-week therapy [5, 6, 27]. The rule of thumb is that for every 100 IUs of vitamin D taken daily, the blood level of 25(OH)D is raised by approximately 1 ng/mL. For maintenance of optimal levels after treating the deficiency, patients are recommended 50,000 IUs of vitamin D2 or vitamin D3 once every 2 weeks. A study in patients on this regimen for up to 6 years showed that they maintained their blood levels of 25(OH)D in the target range of 40–60 ng/mL without any toxicity [5, 6, 27]. Obese women with a BMI >30 need at least two to three times more vitamin D to both treat and prevent recurrent vitamin D deficiency [7, 27].
Fall Prevention
Fall prevention programs have a dramatic effect on reducing risk for osteoporotic fractures in at-risk populations. Improvement in vitamin D status improves proximal muscle strength, thereby reducing risk for falls [34–36]. Exercise is also important for maintenance of bone health throughout life. Falls are a major cause of skeletal fracture in adults over the age of 50 and improvement in hip girdle muscle tone stabilizes the body and reduces fracture risk [35, 36]. The NOF endorses lifelong activity at all ages [19]. Weight-bearing exercise helps to maintain and increase BMD as well as muscle mass and muscle tone, thereby reducing risk of falling and fracture. Weight-bearing exercise includes walking, jogging, Tai Chi, dancing, tennis, and volleyball playing. It is the pounding on the ground that translates into stimuli to help maintain BMD in the hip and lumbosacral spine as well as improve muscle function in the legs and girdle region. This author recommends walking three to five miles a week, which is a simple yet effective exercise [37, 38].
Smoking and Alcohol Consumption
Cigarette smoking has many detrimental health effects, one of which is increasing risk for bone loss. Thus initiating a smoking cessation program for all with tobacco use disorder is beneficial to bone health [23, 39]. Moderate alcohol consumption has been associated with normal or slightly higher BMD and lower risk of fracture in postmenopausal women. However, alcohol intake of more than two drinks a day for women increases risk for falling and may have a detrimental effect on the skeleton, increasing risk for fracture [22].
Pharmacologic Therapy
Recommendations for Who Should Be Treated
It is generally recommended and endorsed by the NOF that all patients being considered for treatment of osteoporosis should also be counseled on risk factor reduction including improving calcium and vitamin D intake, encouraging exercise especially walking three to five miles a week and cigarette smoking cessation [19, 27–29, 40]. The NOF guidelines recommend anti-fracture treatment initiation in postmenopausal women and those over 50 in the following situations:
History of a hip or vertebral fracture (clinically apparent or found on vertebral imaging). The BMD T score is not as important in these patients in predicting future risk of fracture. Patients with spine and hip fractures have a reduced risk for further fracture with pharmacologic therapy.
BMD T score ≤ −2.5 at the femoral neck, total hip, or lumbar spine.
Low bone mass (BMD T score between −1.0 and −2.5 at the femoral neck or lumbar spine) and a 10-year fracture probability of ≥3 % for hip fracture or ≥20 % for a major osteoporotic fracture, based on the US-adapted WHO FRAX algorithm. The NOF however notes that there are relatively few studies confirming fracture risk reductions with pharmacotherapy in this group of patients with low bone mass [19].
FDA-Approved Drugs for Osteoporosis
Calcitonin (Brand Name Miacalcin or Fortical and Generic Calcitonin)
The first drug approved by the FDA in the United States was salmon-calcitonin. It was approved for the treatment of osteoporosis in women who were at least 5-year postmenopausal when alternative treatments were not suitable. It reduces vertebral fracture occurrences by about 30 % in those with prior vertebral fracture but has not demonstrated any efficacy for reducing risk of nonvertebral fractures. It is given as 200 IU intranasally or subcutaneously by injection. Because of its limited benefit in only marginally reducing vertebral fractures, this medication is rarely used in the treatment of postmenopausal osteoporosis [43–45].
Hormone Replacement Therapy (Estrogen Alone or Estrogen Plus Progestin)
Loss of estrogen production that is surgically induced, medically induced, or caused by natural menopause results in a significant increase in bone resorption activity causing on average a 3–4 % decrease BMD in the spine and 2–3 % decrease in BMD in the hip that continues throughout the life of the patient although at a slower rate as the bone mineral content continues to decline. Thus within a decade after menopause, a woman can lose as much as 30–40 % and 20–30 % of their BMD in their spine and hip, respectively. Several estrogen therapies have been approved for the prevention of postmenopausal osteoporosis starting in 1986. Women who have an intact uterus require addition of progestin to their hormonal regimen to reduce the risk for endometrial cancer that can result from unopposed estrogen therapy.
The Women’s Health Initiative (WHI) hormonal trials, consisting of two large and long-running randomized, controlled trials, reported that postmenopausal women receiving 0.625 mg of conjugated equine estrogens with and without 2.5 medroxyprogesterone acetate (MPA) for 5 years had a significant 34 % reduction in clinical vertebral fractures and 23 % reduction in hip fractures compared to those on placebo [46]. Due to concerns raised by the WHI about increased cardiovascular [47] and breast cancer risks with hormonal therapies (HT), the use of systemic conventional dose hormonal therapy for postmenopausal osteoporosis prevention has declined starting in 2002, and this issue is discussed in more detail in other chapters of this book. While lower estrogen doses are also FDA approved for osteoporosis prevention, data on fracture risk reduction efficacy of lower estrogen dose hormonal regimens are lacking and the NOF has taken the position that risks of low-dose hormonal regimens should be considered comparable to conventional doses until studies have shown them to be safer. The FDA recommends non-estrogen therapies be considered as first line for prevention of osteoporosis in postmenopausal women who have no other indication for HT. As to women receiving systemic hormone therapy for relief of vasomotor symptoms, skeletal protection can be assumed with traditional dosing and is presumed with low-dose regimens. Rapid bone loss however can resume with cessation of postmenopausal HT and alternative bone sparing agents must be considered when indicated based on fracture risk assessment [19]
Estrogen Agonist/Antagonist (Formally Known as a Selective Estrogen Receptor Modulator (SERM); Brand Name Evista; Generic Raloxifene)
Raloxifene (60 mg daily) mimics estrogen effect on the skeleton while having an antagonist effect on the uterine endometrium and breasts [48]. It was found to reduce risk of vertebral fractures by about 30 % in patients with the prior vertebral fracture and by about 55 % in patients without a prior vertebral fracture over 3 years. It is not been demonstrated however to reduce risk of nonvertebral fractures. Raloxifene is approved by the FDA for both prevention and treatment of osteoporosis in postmenopausal women. It also has the indication for reduction in risk for invasive breast cancer in postmenopausal women with osteoporosis [48–51]. Raloxifene side effects include exacerbation of hot flashes and leg cramping as well as a small increase in the risk of venous thromboembolism and stroke [52–56]
Tissue-Selective Estrogen Complex: Conjugated Estrogens/Bazedoxifene (Brand Duavee, Conjugated Estrogens Pared with a SERM)
The concept is to combine conjugated estrogen with bazedoxifene, a SERM with tissue-selective estrogen agonist (on skeleton) and estrogen antagonist (on the uterine endometrium) activities; the goal is for having estrogen benefit on the skeleton and treating moderate to severe hot flashes while blocking estrogen’s action on the uterus and eliminating the need for a progestin in women with an intact uterus. This combination medication was approved by the FDA for treatment of moderate to severe menopausal hot flashes and prevention of postmenopausal osteoporosis. Twelve-month trials with this therapy in newly postmenopausal women have shown an increased BMD in the lumbar spine by 1.51 % and by 1.21 % in the hip compared to a placebo [19]. As with estrogens and other SERMs, this therapy is associated with risk for venous thromboembolism. Side effects include, among others, nausea, dyspepsia, and abdominal pain.
Bisphosphonates (Generic and Brand Names Alendronate, Fosamax; Risedronate, Actonel; Zoledronic Acid, Reclast; Ibandronate, Boniva)
The first use of a bisphosphonate was for the treatment of Paget’s disease. Etidronate was the first bisphosphonate that was demonstrated, when used in a cyclical fashion, to improve BMD. However, this drug when taken daily for a prolonged period of time also caused osteomalacia [19].
While bisphosphonates have been in use since the 1970s for other indications, Alendronate was the first of the second-generation bisphosphonates to be approved by the FDA in 1995 for increasing bone mass in women and men with osteoporosis and for the treatment and prevention of osteoporosis in women [57, 58]. It was also approved for the treatment of osteoporosis in those on chronic glucocorticoid therapy [59]. The dose of 10 mg daily or 70 mg weekly taken in the morning on an empty stomach with water was found to improve BMD in lumbar spine by 2–3 % and in the hip by 1–2 % annually. This translated into reducing the incidence of fractures in the spine and hip by about 50 % over 3 years in patients with a prior vertebral fracture or in patients who had osteoporosis at the hip [57].
Several other bisphosphonates were subsequently approved by the FDA for the treatment and prevention of postmenopausal osteoporosis. These include the third-generation risedronate, various dose regimen of which are also approved for prevention and treatment of glucocorticoid-induced osteoporosis (5 mg daily, 35 mg weekly, 75 mg on two consecutive days every month, or 150 mg monthly) [60–64] ibandronate (150 mg orally monthly or 3 mg every 3 months by intravenous injection) reduces incident vertebral fractures by about 50 % over 3 years, but reduction in risk of nonvertebral fracture with this bisphosphonate has not been proven [65–68].
Zoledronic acid is the newest and most potent of available bisphosphonate which reduces incidence of vertebral fractures by 70 %, hip fractures by 41 %, and nonvertebral fractures by 25 % over 3 years in patients with vertebral or hip osteoporosis [64, 69–75]. It offers convenient dosing 5 mg by intravenous infusion over at least 15 min annually for treatment and biennially for osteoporosis prevention.
The major side effect of the second-generation nitrogen-containing bisphosphonates when given orally was symptoms of gastritis that could lead to gastric bleeding [57, 75]. All bisphosphonates can affect renal function and are contraindicated in patients with an estimated GFR below 30–35 mL/min. Atrial fibrillation has also been associated with bisphosphonate use and a meta-analysis suggested the relative risk 1.53 with 95 % confidence limits (1.17–2.0) [11, 12]. However, more concerning are reports that both oral and intravenous bisphosphonate therapy increases risk for atypical subtrochanteric femoral fractures and for osteonecrosis of the jaw (ONJ) [12, 72–80]. Although it has been reported that ONJ is a very rare occurrence 1 in 5000–10,000 cases [71–73], I have seen 14 premenopausal and postmenopausal women who have been on a bisphosphonate for as little as 2 years with these serious side effects. My suspicion is that these side effects are underreported. Often women who have had a subtrochanteric femoral fracture will often experience an additional fracture on this contralateral side requiring hardware placement to stabilize both femurs. For those patients who are being considered for bisphosphonate therapy, it is reasonable for them to have any type of invasive dental procedure performed before prescribing bisphosphonates especially those that are given intravenously. There is no standard recommendation for when to begin bisphosphonate therapy after an invasive dental procedure. It would be reasonable to wait at least 1–2 months after the procedure and healing has been completed. There is also no recommendation for those who are on a bisphosphonate and plan to have a dental procedure as if and when they should stop the bisphosphonate. It probably does not matter since the bisphosphonate is already in the skeleton however to provide a level of comfort to both patients and the dentist. I usually recommend that they stop 1–2 months before the dental procedure and wait 1–2 months after the procedure before restarting their medication. Bisphosphonates have a very long half-life in the skeleton. They affect osteoclast function and ingestion of a bisphosphonate by an osteoclast causes apoptosis, i.e., its death. Bone biopsies performed in patients with subtrochanteric femoral fractures have revealed that there was very little if any bone remodeling activity at the site of the fracture [80]. A study evaluating micromechanical properties in patients treated with long-term alendronate therapy revealed that the therapy altered the size of the calcium hydroxyapatite crystals and compromised the micromechanical properties of the bone matrix, i.e., decrease skeletal strength. This was thought to be in part due to differences in the crystallinity irrespective of the mineral amount and mineral maturity [80]. Concern about increased risk for ONJ and subtrochanteric femoral fractures led to the FDA expert panel to recommend that bisphosphonate should be used short-term, i.e., no more than 5 years. They noted that patients on a bisphosphonate for 5 years who were then switched to a placebo demonstrated a modest decrease in BMD and the femoral neck during the first 1–2 years and then stabilized, whereas BMD in the lumbar spine continued to increase despite discontinuation of bisphosphonate therapy [12, 71–80]. This has introduced the concept of a drug holiday. However, there are no specific recommendations for how long the holiday should last and some physicians will stop for 1 or 2 years and then restart, while most physicians simply have the patient on a permanent holiday never restarting antiresorptive therapy.
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