OVERVIEW

Osteoporosis is a disease of bone. It simply means porous bone. An unwanted consequence of having weak bones or osteoporosis is having a fracture. These are termed insufficiency or fragility fractures and usually occur in the hip, spine, pelvis or forearm. Although the curved spine that typifies severe osteoporosis is often minimized by being characterized as a normal part of aging or by association with certain loveable old relatives , it is often a sign of  a devastating disease. Half of all people who suffer a osteoporosis-related hip fracture end up in a nursing home and one-fourth die.

BONE DENSITY

PEAK BONE DENSITY

Bone mineral density (BMD) in women depends primarily upon achievement of peak bone mass years before menopause (premenopausal). Low BMD in a premenopausal woman may result from the attainment of a peak bone mass that is below average due to genetic predisposition, Illnesses, medications that negatively impact bone density accrual. "Peak bone mass" is usually defined as the maximum BMD achieved by age 40 years, as measured by dual-energy x-ray absorptiometry (DXA or DEXA scan). In healthy girls, the peak period of bone mass accrual occurs between ages 11 and 14 years. Although 95 to 100 percent of peak bone mass is acquired by the late teen years, studies have documented continued small gains occurring between the ages of 20 and 29 years. Population-based studies suggest that women attain peak bone mass at the proximal femur in their 20s and at the spine and forearm around age 30 years. Attainment of peak bone mass varies according to:

• gender
• ethnicity
• body size
• bone site

Low BMD in a premenopausal woman may result from the attainment of a peak bone mass that is below average due to

• genetic predisposition
• Illnesses
• medications that negatively impact bone density accrual

"Peak bone mass" is usually defined as the maximum BMD achieved by age 40 years, as measured by dual-energy x-ray absorptiometry (DXA or DEXA scan).

Ethnicity

Chinese American women appear to attain peak bone mass at a later age. Thus, when interpreting BMD measurements in premenopausal women, the possibility that peak bone mass has not yet been achieved must always be considered.[1] Highest incidence of fractures is in Sweden, Denmark and Norway. (539 to 574 per 100,000)[2] Asian men have half the fracture risk of Caucasian men.  Japanese have a high incidence of vitamin D deficiency.

Fragility fracture

A fragility fracture is a fracture (broken bone) resulting from a fall from standing height or less.  Our bodies should be able to sustain a fall from this height without a fracture unless there is an underlying cause that makes the bones fragile.  The most common areas involved include the hip, spine, wrist as well as humerus, rib and pelvis. The first fracture is a warning sign! It should result in immediate screening and, if indicated, management and treatment for osteoporosis.[3]

Certain skeletal locations, including the skull, cervical spine, hands, feet, and ankles, are not associated with fragility fractures. Stress fractures are also not considered fragility fractures, as they are due to repetitive injury.[4]

Low-trauma fracture

Low-trauma fracture is another term for fragility fracture. Premenopausal women may come to medical attention because of a fragility fracture. As in all cases of unusual fracture, the diagnosis of osteoporosis should be considered only after osteomalacia (undermineralization due to causes such as severe vitamin D deficiency or hypophosphatemia) and other causes of pathological fracture (eg, malignancy, avascular necrosis, fibrous dysplasia, other bone lesion) have been ruled out. After ruling out these pathologies, any fracture in an adult woman (aside from a fracture of the digits, skull, or face) that occurs from a standing height or less, without major trauma such as a motor vehicle accident, can be considered a low-trauma or fragility fracture. Such women may have decreased bone strength and may be considered to have osteoporosis, irrespective of BMD.[5]

Clinical risk factors for fracture[6]

• Advancing age
• Previous fracture
• Glucocorticoid therapy (see GIOP)
• Parental history of hip fracture
• Low body weight
• Current cigarette smoking
• Excessive alcohol consumption
• Rheumatoid arthritis

Risk factors for osteoporosis

A study published in Feb 2017 “was to determine whether smoking, drinking coffee and alcohol in menopausal women contribute to the reduction of bone mass and osteoporosis, as well as the impact of physical activity on bone mass.” Their conclusion was “smoking is an independent risk factor for osteoporosis in postmenopausal women, and physical activity is a protective factor for bone mass retention. Through education and certain preventive measures the importance of these factors on bone health should be stressed  from the earliest period.”[7]

Coffee

High consumption of coffee has been suggested to contribute to the development of osteoporotic fractures. Results of previous fracture studies have been inconsistent, and a comprehensive study is needed. The longitudinal population-based Swedish Mammography Cohort, including 61,433 women born in 1914-1948, was followed up from 1987 through 2008. Coffee consumption was assessed with repeated food frequency questionnaires. During follow-up, 14,738 women experienced fractures of any type, and 3,871 had a hip fracture. In a subcohort (n = 5,022), bone density was measured and osteoporosis determined (n = 1,012). After multivariable adjustment, there was no evidence of a higher rate of any fracture (hazard ratio per 200 mL coffee = 0.99; 95% confidence interval: 0.98, 1.00) or hip fracture (hazard ratio per 200 mL coffee = 0.97, 95% confidence interval: 0.95, 1.00) with increasing coffee consumption. A high coffee intake (≥4 cups daily) versus a low intake (<1 cup daily) was associated with a 2%-4% lower bone density, depending on site (P < 0.001), but the odds ratio for osteoporosis was only 1.28 (95% confidence interval: 0.88, 1.87). Thus, high coffee consumption was associated with a small reduction in bone density that did not translate into an increased risk of fracture.[8]

Nevertheless, in a study of 1222 home-dwelling women aged 70-73 years where lifelong occupational and leisure time physical activity, calcium intake, smoking, alcohol intake and medical history were obtained by a self-completed questionnaire and outcome measures were broadband ultrasound attenuation (BUA) of the calcaneus and bone mineral density (BMD) of the radius measured once in 1997-1998, women with BMI < or = 25.1 kg m(2) had lower BUA (p < 0.0001) and radial BMD values (p < 0.0001) than women with higher BMI. Lifestyle factors associated with BUA in the leanest women included coffee intake > or = 5 cups/day (RR 1.7; 1.1 to 2.7). So, high coffee intake may increase the risk of lower bone density in lean elderly women.[9]

In a case control study of 100 matched subjects, in  terms of consumption of coffee, a statistically significant difference was not found between the group of cases and control group (χ2=0.615, p=0.735). It can be observed that roughly the same number of women in both groups consumed coffee ≥ 3 cups/day, in a group of cases, 32% in the control group 27%. Moderate, or 1-3 cups/day consumed 37% of the women in group of cases, and 39% of respondents in control group. Coffee did not drink 31% of the women in group of cases, and34% of the control group.[10]

From R Bijelic et al. Risk Factors for osteoporosis in postmenopausal women.. Med Arch. 2017 Feb; 71(1): 25-28

Alcohol

Heavy alcohol use was associated with increased hip fracture risk.

Smoking

(From Pouresmaeli)

Gender and osteoporosis

Men have half the fracture risk as women but higher mortality when hip is fractured.[10]

Previous fracture

20% of vertebral fracture patients will fracture again in the next year.[12]

Medications that cause osteoporosis

Aluminum

Anticoagulants (heparin)

Anticonvulsants

Aromatase inhibitors

Barbiturates

Cancer chemotherapy

Glucocorticoids (>=5 mg. A day prednisone > 3 mos

GnRH

Depo-progesterone

Lithium, cyc A and tacrolimus

Methotrexate

Parenteral nutrition

PPI

SSRI

Tamoxifen

Thiazolidinediones

Thyroid hormone (in excess)

Inhaled glucocorticoids

Osteoporosis, a condition that causes bones to become fragile and prone to fracture, is more common in patients with chronic obstructive pulmonary disease (COPD) than the general population. In addition, inhaled corticosteroids (ICSs), which are recommended for COPD treatment alongside other agents, may also have a negative effect on bone strength and may further increase fracture risk for these patients. Previous studies looking at the association between ICS use and bone fracture risk have given mixed results, A review of published studies of ICS versus placebo in patients with COPD lasting at least 12 months, with the hope of identifying further details of the ICS-bone fracture relationship found no difference in the fracture risk for patients receiving ICSs compared with those receiving placebo.[13]

In a meta-analysis, twenty-three trials were reviewed; 11 papers fit the inclusion criteria and were assessed for the main analysis. Quality scores for the randomized controlled trials (RCTs) were high for various types of studies. Inhaled corticosteroids (ICS) effects on BMD were globally assessed and found to be deleterious. A single study evaluated the impact of ICS on hip fracture and reported an increased OR of 1.6 (1.24; 2.03). Budesonide (BUD) appeared to be the ICS inducing the less deleterious effects on bone, followed by beclomethasone dipropionate (BDP) and triamcinolone (TRI). [14]

Prolonged use of systemic corticosteroids leads to reduced bone mineral density and osteoporosis, in turn increasing the risk of minimal trauma fractures with their associated morbidity and mortality in elderly populations. However, the effect of inhaled corticosteroids on bone mineral density has been debated in the medical literature. Data was collected from the Hunter Community Study, a longitudinal cohort of Australians aged 55-85. Simple and multiple linear regression methods were used to test the cross-sectional association between inhaled corticosteroids and calcaneal bone mineral density measured with quantitative ultrasound at baseline. A causal diagram was used to determine the minimally sufficient number of co-variates necessary to determine the unconfounded effect of inhaled corticosteroids on bone mineral density  including gender, body mass index, smoking, asthma, alcohol use, age, physical activity, and diet. Results: There were 152 (6.8%) patients on inhaled corticosteroids and 2098 (93%) controls. Simple and multiple linear regression methods showed a non-significant effect of inhaled steroids on BMD with slight decrease of BMD -0.010 g/cm2 (95% CI -0.042 to 0.022, P = .55) and -0.013 g/cm2 (95% CI -0.062 to 0.036, P = .61) respectively. Age, gender, body mass index, and smoking were stronger predictors of BMD. Conclusions: No statistically significant relationship was detected between the use of inhaled corticosteroids and reduced bone mineral density in this observational study of a cohort of older Australians.[15]

Product information of budesonide (Pulmicort) lists postmarketing and/or case report side effects that include avascular necrosis of femoral head,  bruise, cataract, depression, glaucoma, growth suppression, hypercorticoidism, increased intraocular pressure, irritability, nervousness, osteoporosis - all known systemic steroid side effects.[16]

The skeletal effects of inhaled glucocorticoids are poorly understood. Children with asthma treated with inhaled glucocorticoids have lower growth velocity, bone density, and adult height. Studies of adults with asthma have reported variable effects on BMD, although prospective studies have demonstrated bone loss after initiation of inhaled glucocorticoids in premenopausal women.  ; the risk of vertebral and non-vertebral fractures is greater in subjects treated with the highest doses in the majority of studies. Patients with COPD have lower BMD and higher fracture rates compared to controls, however, the majority of studies have not found an additional detrimental effect of inhaled glucocorticoids on bone. While the evidence is not conclusive, it supports using the lowest possible dose of inhaled glucocorticoids to treat patients with asthma and COPD and highlights the need for further research on this topic.[17]

Genetic causes of osteoporosis

Idiopathic osteoporosis (IOP) is reserved for the subset of women with no apparent etiology or known secondary cause. Some women with IOP may have an adult presentation of a primary or genetic etiology of bone fragility [17].

• osteogenesis imperfecta
• hypophosphatasia (associated with osteomalacia)
• osteoporosis-pseudoglioma syndrome /LRP5 mutations 
• Marfan syndrome
• Ehlers-Danlos syndrome

Guidelines

Diagnostic Assessments[18]

1. Measure height annually using a stadiometer
2. Measure bone mineral density (BMD):

1. In women age 65 and older
2. In men age 70 and older
3. In postmenopausal women and men above age 50-69 based on risk profile
4. In postemenopausal women and men age 50 and older who have had an adult age fracture, to diagnose and determine the degree of osteoporosis
5. At dual-energy X-ray absorptiometry (DXA) facilities using accepted quality assurance measures

3. Vertebral imaging
4. Low-trauma fracture during adulthood (50 and older)
5. Historical height loss
6. Prospective height loss
7. Recent or ongoing long-term glucocorticoid treatment
8. Check for secondary causes of osteoporosis
9. Biochemical markers

Other assessments

• Lab

• 25OHVit D
• CMP
• CBC

• Other lab if z-score is low

• Urine cortisol
• PTH
• 24 hour urine calcium
• Protein electropheresis (if hypercalcemia is present)

Vitamin D

Based on vitamin D level. Assessment is based on 4 groups:

1. Vitamin D sufficiency = 25(OH)D concentration greater than 20 ng/mL (50 nmol/L)
2. Vitamin D insufficiency is defined as a 25(OH)D concentration of 12 to 20 ng/mL (30 to 50 nmol/L)
3. Vitamin D deficiency is defined as a 25(OH)D level less than 12 ng/mL (30 nmol/L)
4. A "risk" of vitamin D toxicity is defined as a 25(OH)D level >100 ng/mL

Vitamin D Testing

Widespread testing is associated with potentially unnecessary treatments with supplements, retesting and increased medical costs. On average, a vitamin D deficiency test can cost $50, typically covered by health insurance. In 2014 in upstate New York, an estimated $33 million was spent on vitamin D testing, according to an Excellus BCBS infographic, “Vitamin D Tests.”[19]

The USPSTF concluded that current evidence is insufficient to assess the benefits and harms of screening for vitamin D deficiency in asymptomatic adults. Compared with placebo or no treatment, vitamin D was associated with decreased mortality; however, benefits were no longer seen after trials of institutionalized persons were excluded. Vitamin D treatment was associated with a possible decreased risk for at least 1 fall and the total number of falls per person but not for fractures. None of the studies examined the effects of vitamin D screening versus not screening on clinical outcomes.[20]

African Americans and Vitamin D Testing

Diagnosis

Osteoporosis is characterized by

•  low bone mass
• microarchitectural disruption
• increased skeletal fragility.

A clinical diagnosis of osteoporosis may be made in the presence of either:

• Fragility fracture, particularly at the spine, hip, wrist, humerus, rib, and pelvis
• or T-score ≤-2.5 standard deviations (SDs) at any site based upon bone mineral density (BMD) measurement by dual-energy x-ray absorptiometry (DXA)

As another means for diagnosis of osteoporosis in postmenopausal women, the National Bone Health Alliance suggests that a clinical diagnosis of osteoporosis may be made if there is a clear elevated risk for fracture. In the United States, for example, a clinical diagnosis of osteoporosis may be made when the Fracture Risk Assessment Tool (FRAX) 10-year probability of major osteoporotic fracture is ≥20 percent or the 10-year probability of hip fracture is ≥3 percent.

⅓ of vertebral fractures are asymptomatic.[21] 

Treatment

Treatment includes lifestyle measures and pharmacologic therapy.

Lifestyle measures[22]

1. Adequate vitamin D
2. Other diet considerations
3. Exercise
4. Adequate calcium
5. Smoking cessation
6. Counseling on fall prevention
7. Avoidance of heavy alcohol use
8. Avoid, if possible, drugs that increase bone loss, such as glucocorticoids

Calcium

It is a universal recommendation for diet to include adequate calcium intake. This is 1000 mg. A day for men and 1200 mg. For women over 50 and men over 70.[23] Postmenopausal women who are getting adequate calcium from dietary intake alone (approximately 1200 mg daily) do not need to take calcium supplements. Women with inadequate dietary intake should take supplemental elemental calcium (generally 500 to 1000 mg/day) in divided doses at mealtime, such that their total calcium intake (diet plus supplements) approximates 1200 mg/day. There is considerable controversy around the effects of calcium supplements on the risk of cardiovascular disease.

NOF supports Institute of Medicine (IOM) recommendations that men age 50–70 consume 1000 mg/day of calcium and that women age 51 and older and men age 71 and older consume 1200 mg/day of calcium. There is no evidence

that calcium intake in excess of these amounts confers additional bone strength. Intakes in excess of 1200 to 1500 mg/day may increase the risk of developing kidney

stones, cardiovascular disease, and stroke. The scientific literature is highly controversial in this area.

Vitamin D

Vitamin D increases intestinal calcium absorption and renal reabsorption of calcium. Vitamin D is easier to absorb than calcium and can be ingested once a day with or without food.[24]

Vitamin D Supplementation

 Among healthy adults, treatment with vitamin D for 3 years at a dose of 4000 IU per day or 10 000 IU per day, compared with 400 IU per day, resulted in statistically significant lower radial BMD; tibial BMD was significantly lower only with the 10 000 IU per day dose. There were no significant differences in bone strength at either the radius or tibia. These findings do not support a benefit of high-dose vitamin D supplementation for bone health; further research would be needed to determine whether it is harmful.[25]

This guideline updates the 2013 USPSTF guideline, which recommended against daily supplementation of ≤ 400 IU vitamin D3 and ≤ 1000 mg of calcium (D recommendation) in postmenopausal women without osteoporosis because of the increased risk for kidney stones and lack of fracture benefit. There was insufficient evidence to recommend higher doses of vitamin D and/or calcium supplements in postmenopausal women and insufficient evidence for recommendations in men and premenopausal women. Since 2013, only 2 additional RCTs have been published, so it is not surprising that the 2018 recommendations are the same as in 2013.

Clinicians should note that these recommendations only apply to healthy, asymptomatic, community-dwelling adults and not patients with osteoporosis, fragility fractures, or vitamin D deficiency or who are at increased risk for falls. For at-risk patients, it is reasonable to consider vitamin D supplements (> 400 to 2000 IU/d) as recommended by the Institute of Medicine and Endocrine Society. For such patients, vitamin D plus calcium reduces hip fractures by 19% and has been included as adjunct therapy in all fracture-prevention drug trials.[26]

Women should ingest a total of 800-1000 international units of vitamin D daily. Higher doses are required if they have malabsorption or rapid metabolism of vitamin D due to concomitant anticonvulsant drug therapy. Most postmenopausal women with osteoporosis require vitamin D supplementation as it is difficult to achieve goals with diet alone.

The American Geriatrics Society (AGS) and the National Osteoporosis Foundation (NOF) recommends a slightly higher dose of vitamin D supplementation (at least 1000 international units [25 micrograms], and 800 to 1000 international units daily, respectively) to older adults (≥65 years) to reduce the risk of fractures and falls.[27]

Some studies suggest that vitamin D3 increases serum 25(OH)D more efficiently than does vitamin D2. In addition, vitamin D2 is not accurately measured in all vitamin D assays.  For these reasons, we suggest supplementation with vitamin D3, when possible, rather than vitamin D2.[28]

D2	Ergocalciferol
D3	Cholecalciferol

Vitamin D Repletion

For individuals with serum vitamin D levels of 12 to 20 ng/mL, initial supplementation with 800 to 1000 international units (20 to 25 micrograms) daily may be sufficient. A repeat serum 25(OH)D level should be obtained after approximately three months of therapy to assure obtaining the goal serum 25(OH)D level. If goal level is not achieved, higher doses may be necessary.

Efficacy of Vitamin D

 In the largest of trials (Women's Health Initiative [WHI]), subgroup analysis revealed that calcium and vitamin D supplementation was associated with reduced fracture incidence in those individuals who were most compliant. The variable results are likely due to differences in patient populations (community dwelling versus nursing home) and study design. Few trials assess baseline vitamin D levels. Calcium and vitamin D supplementation in individuals who already have adequate calcium intake and normal vitamin D levels is unlikely to be of benefit.[29]

A meta-analysis by  Avenell and colleagues' recent study from the Cochrane

Collaboration, which included 49 853 participants and found a relative risk for hip fracture of 0.84 (CI, 0.74 to 0.96 [P <0.01]) in persons treated with vitamin D plus

calcium. This study and similar meta-analyses constitute good evidence that vitamin D plus calcium (but not vitamin D alone) prevents fractures.

These studies have consistently shown no effect of supplementation with vitamin D and calcium on vertebral fractures.[30]

Other Diet Considerations

1. Celiac disease treat with gluten free diet
2. Protein intake controversial
3. Caffeine

• The results of controlled calcium balance studies in humans indicate that caffeine consumption leads to a small negative calcium balance in individuals with inadequate calcium intakes.[31] The negative shift in calcium balance has been estimated to be about 4–6 mg of calcium per cup of coffee, and is due to a slight decrease in the efficiency of calcium absorption.
• The majority of cross-sectional studies have found no association between caffeine consumption and bone mineral density (BMD).Of the six studies that have examined associations between caffeine consumption and change in BMD over time, four found no effect of caffeine. One found that the consumption of more than 300 mg/d was associated with accelerated loss of BMD, and another found that caffeine consumption was associated with accelerated loss of BMD only in women with calcium intakes less than 744 mg/d.
• Five case-control studies have examined relationships between coffee and caffeine consumption and the risk of hip fracture. None of them found coffee or caffeine consumption to be associated with significantly increased risk of hip fracture.
• Six prospective cohort studies have examined associations between caffeine (mainly from coffee) or coffee consumption and the risk of hip fracture in women. Two studies, one in Finland and one in Japan. found no association. Another study in Norway found that women who consumed at least 9 cups of coffee daily tended to have an increased risk of hip fracture, but only 6.8% of women consumed this much coffee.
• However, three prospective cohort studies in the US found that coffee or caffeine consumption was positively associated with the risk of hip fracture in women.
• In the Framingham cohort, women who consumed more than 2 cups of coffee daily had a 70% higher risk of hip fracture over the next 12 years than women who did not consume caffeinated beverages. In the Nurses' Health Study cohort, women who consumed 4 or more cups of coffee daily had a risk of hip fracture over the next 6 years that was almost three times the risk of those who did not drink coffee. A prospective cohort study of women 65 years of age and older found that a 190 mg increase in caffeine consumption increased the risk of osteoporotic fracture by about 20%.
• Given the multifactorial etiology of osteoporosis, the impact of coffee or caffeine consumption on the risk of osteoporosis is not clear. However, currently available evidence suggests that ensuring adequate calcium and vitamin D intake and limiting coffee consumption to 3 cups/d (300 mg/d of caffeine) may help reduce the risk of osteoporosis and osteoporotic fractures, particularly in older adults.
• On average, an 8-ounce (236-ml) cup of decaf coffee contains up to 7 mg of caffeine, whereas a cup of regular coffee provides 70–140 mg.[32]

Exercise

Women with osteoporosis (or who are seeking to prevent it) should exercise (prudently) for at least 30 minutes three times per week. In prospective cohort studies, exercise was associated with a reduced risk of hip fracture in older women. In a meta-analysis of 10 trials, exercise reduced the occurrence of overall fractures in older adults (4.8 versus 10.9 percent in the control group; relative risk [RR] 0.49, 95% CI 0.31-0.76). The reduction in vertebral fractures was not statistically significant (three trials, 18 versus 30 percent; RR 0.56, 95% CI 0.30-1.04). This may be related to the small number of patients included in the vertebral fracture trials.

Exercise also has beneficial effects on BMD in premenopausal and postmenopausal women. A meta-analysis of 43 randomized trials (4320 participants) of exercise and BMD in postmenopausal women showed a significant positive effect of exercise on BMD at the lumbar spine (LS) (mean difference 0.85, 95% CI 0.62-1.07) and trochanter (mean difference 1.03, 95% CI 0.56-1.49) compared with controls. A variety of exercise types, including resistance training, jogging, jumping, and walking, was effective. The most effective type of exercise for BMD of the femoral neck was non-weight-bearing, high-force exercise (eg, progressive resistance strength training), whereas a combined program (mixture of more than one exercise type) was most effective for LS BMD. The meta-analysis was limited by loss to follow-up and the poor quality of allocation concealment and blinding.

Overall, the beneficial effect of exercise on bone density is small. However, these changes reflect areal BMD measurements. It is still uncertain how long-term exercise affects other measures of bone architecture. Therefore, if exercise does reduce the risk of fracture, it may relate to changes in parameters other than areal bone mass or to increased muscular strength and decreased risk of falls.

Intense exercise -- There is no convincing evidence that high-intensity exercise, such as running, is of greater benefit than lower intensity exercise, such as walking. Because enjoyment of the regimen is important (the benefits of exercise are quickly lost after the woman stops exercising, we recommend that women pick a regular weight-bearing exercise regimen that they enjoy to facilitate long-term compliance. Excessive exercise in premenopausal women may lead to weight loss and amenorrhea, thereby causing osteoporosis.

Cessation of smoking

Smoking cessation is strongly recommended to all women concerned with their skeletal health because smoking cigarettes accelerates bone loss. One study, as an example, evaluated female twins who were discordant for smoking. Smoking one pack per day throughout adult life was associated with a 5 to 10 percent reduction in bone density. Smoking may also negate the beneficial effect of estrogen therapy in postmenopausal women. This may be mediated in part by acceleration of the metabolism of estrogen, thereby lowering serum estrogen concentrations.

Fall prevention

Falls are the leading cause of injury-related deaths and emergency department visits and account for over $30 billion in direct medical costs. For older persons, the consequences of falls can be devastating, including reduced mobility, functional decline, and loss of independence. With our aging population, it will become increasingly important to find ways to reduce falls among our vulnerable elders.[33]

Pharmacologic therapy: Drugs and indications

Approach

Bisphosphonates are recommended as initial therapy because of efficacy, favorable cost, and long-term safety data.[34] This was debated in some sub-groups of patients at the American College of Rheumatology meeting in Atlanta in 2019. Consensus seemed to favor a parathyroid hormone analogue drug as initial therapy for patients with extreme risks.

Bisphosphonate versus denosumab

From Albert SG, Reddy S. CLINICAL EVALUATION OF COST EFFICACY OF DRUGS FOR TREATMENT OF OSTEOPOROSIS: A META-ANALYSIS. Endocr Pract. 2017 Jul: "The most cost-effective initial therapy of postmenopausal osteoporosis is generic oral alendronate or generic parenteral zoledronate. There is no statistically significant difference in efficacy of available drugs to prevent hip fractures." [35]

Estimating Fracture Risk

The effectiveness of fracture prevention increases with advancing age.[35] Economic models suggest that it might be cost effective to treat older women for fracture reduction who have life expectancies of as little as 2 years. If life expectancy is less than 1 year, pharmacologic osteoporosis treatment should not be provided.

The FRAX tool[36] (University of Sheffield) is the most validated and commonly used fracture prediction model. Individuals with a 10-year estimated risk of major osteoporotic fracture between 10% and 20% are at moderate fracture risk, whereas individuals with an estimated risk of at least 20% have a high risk for fracture.

Contraindications to oral bisphosphonate therapy

1. Achalasia
2. Esophageal stricture
3. Esophageal varices
4. Barrett’s esophagus
5. Inability to follow bisphosphonate dosing directions
6. Gastric bypass Roux-en-Y

Contraindications to oral or IV bisphosphonate therapy

1. GFR <30-35 ml/min

Indications for treatments

In the United States, pharmacologic therapy is recommended in individuals with (1) hip or vertebral fracture, (2) BMD T-scores less than or equal to −2.5, or (3) BMD T-scores between −1.0 and −2.5 and a 10-year probability of hip fracture of at least 3% or 10-year probability of major osteoporotic fracture of at least 20%.[37]

Alendronate	Zoledronic acid	Tymlos (abaloparatide)	Forteo (teraparatide)	Prolia
Postmenopausal osteoporosis Osteoporosis in men Glucocorticoid induced osteoporosis Paget disease	Bone mets Hypercalcemia Multiple myeloma Osteoporosis glucocorticoid induced treatment and prevention Osteoporosis prevention and treatment Paget disease	Osteoporosis, postmenopausal, fracture risk reduction	Osteoporosis in men and postmenopausal women or glucocorticoid induced	Hypercalcemia Malignancy Androgen deprivation bone loss in men w prostate cancer Aromatase inh in breast cancer Giant cell bone tumor Postmenopausal osteoporosis in women and men

Choice of Treatment

The number of older adults (mean age, 85 years) needed to treat (NNT) to prevent 1 hip fracture is approximately 200. Although oral bisphosphonates are the most cost-effective

therapy, other considerations in choosing therapy for older and more frail patients include pill burden and comorbidities.[38]

Efficacy of drugs

	Alendronate	Zoledronic acid	Risedronate	Ibandronate
Reduction in hip fracture risk	50% over 3 yrs w op hip site	41% over 3 yrs
Reduction in vertebral fracture risk	50% over 3 yrs with prior vert fx; 48% wo fx	70% in 1 yr	41-49%	50% over 3 yrs

	Raloxifene	Denosumab	Teriparatide
Reduction in hip fracture risk	50% over 3 yrs w op hip site	40%
Reduction in vertebral fracture risk	30% over 3 yrs with prior vert fx; 55% wo fx	68%

Duration of treatment

The ACP encourages clinicians to treat patients with osteoporosis for 5 years and recommends against monitoring BMD during this 5-year treatment period. The ACP does not address BMD monitoring after completion of treatment.[39] Dr. Berry states: a post hoc analysis of FIT (Fracture Intervention Trial), a large study of postmenopausal women randomly assigned to receive alendronate versus placebo, found a similar fracture reduction among participants taking a bisphosphonate who lost bone as compared with women taking a bisphosphonate who gained bone. Thus, it is unclear that monitoring BMD while taking an osteoporosis medication improves outcomes.[40]

Cost of drugs

Cost of drugs ($)

	Month	year	Pill/dose
Alendronate	10[41]	120
Zoledronate	17[42]	200
Raloxifene	196	2352	7
Prolia	166[43]	2000
Forteo	2598	31,176‬
Tymlos	1401	16,812
Evenity	935	11220	935
Ibandronate	130[44]	1560

Cost of fractures

Average annual cost of hip fracture	32,687
Average annual cost of vertebral fracture	14,717

Cost comparison

In a meta-analysis of 43 evaluable randomized, double-blind, placebo-controlled trials in 71,809 postmenopausal women comparing fracture frequency, cost comparisons were evaluated for a treatment strategy assuming generic alendronate as first-line therapy. Denosumab and teriparatide showed benefits in vertebral fracture reduction over alendronate at incremental costs respectively of $46,000 and $455,000 per fracture prevented. Zoledronate, recently released as a generic, would be either less expensive or comparable in cost. None of the alternate medicines were statistically better in preventing hip fractures. Teriparatide was more effective in preventing nonvertebral fractures at an incremental cost of $1,555,000.[45]

Trends in treatment

An estimated 21.3million prescriptions for oral bisphosphonates were dispensed in U.S. retail pharmacies in 2002 that increased 46% to a peak of 31.0million in 2007 and 2008, and declined by 53% in a four year-period to 14.7million in 2012. Sales data (number of packages sold in all settings of care) showed parallel trends (66% increase from 2002 through 2007 and 51% decrease from 2007 through 2012). Similarly, intravenous bisphosphonate sales for osteoporosis treatment grew 3.8-fold from 149.5 thousand packages in 2007 to 561.6 thousand in 2010, followed by a 22% decrease in 2012.[46]

Bisphosphonates

Alendronate

Renal disease patients

Contraindicated if GFR < 35

U Liberman et al. Effect of oral alendronate on BMD and incidence of fractures in postmenopausal women. NEJM 11/30/1995

Zolendronic acid

Renal dosing

Contrandicated if GFR < 30

Romosuzumab

Renal dosing

No dosage adjustment necessary; patients with eGFR <30 mL/minute/1.73 m2 or receiving dialysis should be monitored closely for hypocalcemia.[47]

Abaloparatide

Renal dosing

No dosage adjustment necessary.[48]

Schedule for monitoring lab on osteoporosis drugs

Denosumab	6 mos	BMP
Zoledronic acid	1 year	BMP
Alendronate	1 year	BMP
Teriparitide

Risks of antiresorptive agents

ONJ

Introduction

Medication-related osteonecrosis of the jaw (MRONJ), which was first described in 2002, is a relatively uncommon but potentially serious side effect of treatment with osteoclast inhibitors, such as intravenous high-potency bisphosphonates and denosumab, which decrease the risk of skeletal-related events in patients with cancer and metastatic bone disease. The increased dose intensity of osteoclast inhibitors typically prescribed for cancer indications places cancer patients at a substantially higher risk for MRONJ than patients who receive them for other conditions, such as osteoporosis and Paget disease.[49]

Nomenclature and definition

Osteonecrosis associated with bisphosphonate treatment has been referred to by several acronyms, including BRMRONJ (bisphosphonate-related MRONJ), BRON (bisphosphonate-related osteonecrosis), BON (bisphosphonate osteonecrosis), BAMRONJ (bisphosphonate-associated MRONJ), and simply MRONJ. The recognition of jaw necrosis as a complication of other drugs, including the receptor activator of nuclear factor kappa B ligand (RANKL) inhibitor denosumab and antiangiogenic agents, prompted a special committee of the American Association of Oral and Maxillofacial Surgeons (AAOMS) to recommend the term "medication-related osteonecrosis of the jaw" as preferred, and this terminology is also endorsed in joint guidelines from the Multinational Association of Supportive Care in Cancer (MASCC)/International Society of Oral Oncology (ISOO)/American Society of Clinical Oncology (ASCO).

Two working definitions of MRONJ have been proposed:

• A task force convened by the American Society for Bone and Mineral Research (ASBMR) defines MRONJ as the presence of exposed bone in the maxillofacial region that does not heal within eight weeks after identification by a health care professional
• An updated 2014 position paper on MRONJ is available from the AAOMS, which provides an updated definition of the condition, comparative risk estimates of developing MRONJ in patients with cancer and a history of exposure to osteoclast inhibitors and/or antiangiogenic agents, recommendations for prevention measures, and management strategies for patients with established MRONJ.

• Patients may be considered to have MRONJ if the following characteristics are present:

• Current or previous treatment with an osteoclast inhibitor or antiangiogenic agent
• Exposed or necrotic bone in the maxillofacial region that has persisted for more than eight weeks
• No history of radiation therapy to or obvious metastatic disease in the jawbones

The AAOMS definition is preferred and has also been adopted by an international task force on osteonecrosis of the jaw and in joint guidelines on MRONJ from the MASCC/ISOO/ASCO.

PATHOPHYSIOLOGY

Although the first cases of MRONJ were reported over a decade ago, the underlying pathophysiology is not fully elucidated. The leading proposed hypotheses to explain the unique localization of MRONJ to the jaws include remodeling or oversuppression of bone resorption, inhibition of blood supply, constant microtrauma, and infection/inflammation. None of these hypotheses seems to explain all cases.[50]

CLINICAL PRESENTATION

Areas of exposed and necrotic bone, which may remain asymptomatic for weeks, months, or even years, are the consistent hallmark of MRONJ.[51]

INCIDENCE AND RISK FACTORS

Osteoclast inhibitor therapy

 — Although potentially serious, MRONJ is a relatively uncommon complication of therapy with intravenous bisphosphonates and denosumab among patients with advanced malignancy, although it is more common in patients with cancer than in patients who are treated with osteoclast inhibitors for osteoporosis.[52]

The best information on incidence in patients with advanced cancer comes from a review of data on 5677 patients with bone metastases from a wide variety of malignancies enrolled on three identically designed prospective randomized trials comparing zoledronic acid with denosumab for the prevention of skeletal-related events.

The following findings were noted:

• All patients were treated monthly, and the median time to onset of MRONJ was 15 to 16 months
•  Sixty-three patients (1.9 percent) on the denosumab treatment arm developed MRONJ
• 44 (1.3 percent) on the zoledronic acid arm. This difference was not significant between treatment groups (p = 0.08).
• The cumulative incidence rates of MRONJ increased with longer duration of exposure, with an incidence of 0.7 to 1.4 percent during the first year of therapy and increasing to 2 to 3.4 percent with continued treatment beyond one year. When compared with the risk for MRONJ in the placebo arms of the prior intravenous bisphosphonate studies to prevent complications from skeletal metastases (range 0 to 0.19 percent), the risk of MRONJ was 50- to 100-fold higher with the use of modern high-dose monthly intravenous bisphosphonates (ie, zoledronic acid 4 mg monthly).
• Dental extraction preceded the MRONJ event in 63 percent of cases; 82 percent had jaw pain, and a coincident oral infection was present in 48 percent of cases.

Dose, duration, and type of therapy

The risk is higher with intravenous than with oral bisphosphonates and most commonly observed in patients receiving intensive (monthly) parenteral dosing for prevention of skeletal-related events. The incidence of MRONJ observed with osteoporosis dosing of bisphosphonates is markedly lower compared with that observed in oncology patients.[53]

The incidence is higher with longer duration of treatment, particularly when the duration of therapy exceeds four years. This time frame may be shortened by the presence of certain comorbidities, such as chronic glucocorticoid use or concomitant administration of angiogenesis inhibitors.

In another study, the cumulative hazard of developing MRONJ increased according to the duration of intravenous bisphosphonate therapy (0 percent at one year to 11 percent at four years).

Denosumab — As with bisphosphonates, dose, schedule, and duration of osteoclast inhibition are associated with MRONJ risk in patients treated with denosumab.

Oral health-associated risk factors

 — Local risk factors, such as invasive dental procedures or concomitant oral disease increase risk for MRONJ.

Dentoalveolar surgery — Dentoalveolar surgery is a major risk factor for MRONJ, although cases can occur spontaneously without a precipitating oral event.

Among patients with MRONJ, 52 to 65 percent report tooth extraction as the predisposing event:

• In a case-control study of 60 cancer patients exposed to zoledronic acid (20 who developed MRONJ and 40 matched controls who did not), tooth extraction during bisphosphonate therapy was associated with a significant 16-fold increased risk for MRONJ.
• In a longitudinal cohort study of 1621 cancer patients exposed to intravenous bisphosphonates, a history of dental extraction was associated with a significant 33-fold (95% CI 18-60) increased risk for MRONJ.[54]

Management strategies

 — Patients should be counseled regarding the possible occurrence of MRONJ prior to initiating therapy with an osteoclast inhibitor or antiangiogenic agent.

Prevention

Before initiation of an intravenous osteoclast inhibitor — In view of the difficulty in treating established MRONJ, prevention is emphasized.

We agree with joint guidelines from the MASCC/ISOO/ASCO as well as guidelines from the AAOMS, the International Task Force on Osteonecrosis of the Jaw, and the European Medicines Agency (EMA), which all recommend that all patients have a comprehensive dental, periodontal, and oral radiographic examination (when feasible to do so) and preventive dentistry (preemptive extraction of unsalvageable teeth and optimized periodontal health) before beginning therapy with an osteoclast inhibitor.[55]

Asymptomatic patients during therapy

 — During therapy with an osteoclast inhibitor or antiangiogenic agent, oral hygiene status should be closely monitored. All patients should practice good oral hygiene, including daily brushing, flossing, and use of antibacterial oral rinses, and attending recommended dental check-ups, denture fittings, and routine cleanings, to decrease rates of periodontal disease and oral infection. Invasive dental procedures should be avoided, if possible. Patients should be encouraged to stop smoking and curtail alcohol.

Cessation of at-risk medication prior to invasive dental procedures

 — Elective dentoalveolar surgical procedures should be avoided, if at all possible, during treatment with an osteoclast inhibitor. Updated 2019 guidelines from the MASCC/ISOO/ASCO state that there is insufficient evidence to support or refute the need for discontinuation of the osteoclast inhibitor before dentoalveolar surgery. Administration of the osteoclast inhibitor may be deferred at the discretion of the treating clinician, in conjunction with a discussion with the patient and the oral health provider.

In the absence of data, it may also be reasonable to hold the osteoclast inhibitor for two to three months before and after the procedure and to restart once the mucosa is completely healed over, if doing so is consistent with the oncologic goals of care.[56]

Elective dentoalveolar surgery does not appear to be contraindicated in this group. It

is recommended that patients be adequately informed of the very small risk (<1%) of compromised bone healing. The risk of developing MRONJ associated with oral bisphosphonates, while exceedingly small, appears to increase when the duration of therapy exceeds 4 years.101 This time frame may be shortened in the presence of certain comorbidities, such as chronic corticosteroid or antiangiogenic use. If systemic

conditions permit, the clinician may consider discontinuation of oral bisphosphonates for a period of two months prior to and three months following elective invasive dental surgery in order to lower the risk of MRONJ. The rationale for this approach is based on extrapolated data that demonstrate fluctuations of osteoclast function, which is related to bisphosphonate therapy, and recent outcomes studies that show improved outcome of MRONJ treatment with drug

Cessation. The efficacy of utilizing a systemic marker of bone turnover to assess the risk of developing jaw necrosis in patients at risk has not been validated. Therefore the use of systemic markers of bone turnover as a measure of MRONJ risk is not recommended.[57]

For individuals who have taken an oral bisphosphonate for less than four years and have no clinical risk factors, no alteration or delay in the planned surgery is necessary. This includes any and all procedures common to oral and maxillofacial surgeons, periodontists and other dental providers.

In contrast to bisphosphonates, RANK ligand inhibitors do not bind to bone and their effects on bone remodeling are mostly diminished within 6 months of treatment cessation. Inhibition of osteoclastic bone resorption and remodeling. Bisphosphonates (BP), and other antiresorptives

such as denosumab, inhibit osteoclast differentiation and function, and increase apoptosis, all leading to decreased bone resorption and remodeling.Osteoclast differentiation and function plays a vital role in bone healing and remodeling in all skeletal sites, but osteonecrosis of the jaws only occurs primarily within the alveolar bone of the maxilla and mandible.[58]  The central role of bone remodeling inhibition is further corroborated by a similar incidence of ONJ observed with other antiresorptive medications such as denosumab.

Among cancer patients exposed to denosumab, a RANK L inhibitor, the risk of MRONJ ranges from 0.7% - 1.9% (70-90 cases per 10,000 patients). The risk for ONJ among cancer patient exposed to denosumab is comparable to the risk of ONJ in patients exposed to zolendronate. MRONJ risk among osteoporotic patients exposed to IV BP or RANK-L inhibitors.  Studies analyzing patients with osteoporosis exposed to yearly zolendronate therapy for 3 years

reported a risk for MRONJ of 0.017% (1.7 cases per 10,000 subjects). An extension of this study through 6 years did not demonstrate a change in

frequency of MRONJ. In recent reports studying patients exposed to denosumab, the risk for

MRONJ is 0.04% (4 cases per 10,000 subjects). Interestingly, among patients with osteoporosis

exposed to placebo medications, the risk for ONJ ranges from 0% to 0.02% (0-2 cases per 10,000 subjects). The risk for ONJ among patients treated with either zolendronate or denosumab (0.017 – 0.04%) approximates the risk for ONJ of patients enrolled in placebo groups (0%-0.02%).  Based on this current review of data, the risk of developing ONJ among osteoporotic patients exposed to oral, IV BPs, or denosumab is real but remains very low.[59]

Treatment of established medical related osteonecrosis of the jaw (MRONJ)

Discontinuation of osteoclast inhibitors

There are no prospective data to advise the patient or clinician as to the benefits of discontinuing therapy with the osteoclast inhibitor, and there is no consensus as to whether it should be discontinued or continued in patients who develop MRONJ. While discontinuation of the offending agent might stabilize sites of MRONJ, reduce the risk of developing new sites, and control symptoms, treatment discontinuation could also result in a recurrence of bone pain or an increase in skeletal-related events for patients receiving an osteoclast inhibitor in the setting of bone metastases, and a worsening of disease status in patients receiving antiangiogenic agents.[60]

Cessation of at-risk medication therapy prior to tooth extraction or other procedures, which involve osseous injury (eg dental implant placement, periodontal or apical endodontic treatment)

a. Antiresorptive Therapy for Osteoporosis/Osteopenia

 The concept of a drug holiday in individuals receiving oral bisphosphonates or denosumab who

require tooth extractions has been an ongoing area of controversy with little data to support current recommendations.[61]

In 2011 the ADA Council on Scientific Affairs revised their prior recommendation of a drug holiday and suggested that patients receiving lower cumulative doses of bisphosphonate (<2 years) or denosumab may continue antiresorptive therapy during invasive dental treatment. An International ONJ Task Force recommended a drug holiday in patients at higher risk for developing ONJ, including those with greater cumulative bisphosphonate exposure (>4 years), and those with comorbid risk factors such as rheumatoid arthritis, prior or current glucocorticoid exposure, diabetes and smoking until the site has healed. In a 2011 summary document on the long term safety of bisphosphonate therapy for osteoporosis, the FDA determined that there was “no substantial data available to guide decisions regarding the initiation or duration of a drug holiday.”[62]