Antiresorptive medications

Bisphosphonates

Bisphosphonates increase bone mass and reduce the risk of hip, vertebral, and other bone fractures to different degrees (Table 44-1).[23, 34–48] All bisphosphonates share the same basic chemical structure: two phosphonic acid molecules joined by a carbon atom and two side chains. The side chains determine the pharmacokinetic and pharmacodynamic profile of the various bisphosphonates.[34, 35]

Table 44-1 Major studies with various medications for osteoporosis

Medications	Study acronym	Fracture risk reduction		Postmenopausal osteoporosis		Reference numbers
		Hip	Vertebral	Treatment	Prevention
Alendronate	FIT-CFA; FIT-VIA; 10 SIT	Yes	Yes	Yes	Yes	36– 8
lbandronate	BONE	No*	Yes	Yes	Yes	42
Risedronate	HIP: VERT (NA) VERT (MN)	Yes	Yes	Yes	Yes	39–41, 48
Zoledronic acid	Horizon-PIT Horizon-RhT	Yes	Yes	Yes	Yes	43–47
Calcitonin	PROOF	No*	Yes	Yes	No	60, 61
Denosumab	FREEDOM	Yes	Yes	Yes	No	54–57
Raloxifene.,	MORE	No*	Yes	Yes	Yes	58
Teriparatide	PT; EFOS	**	Yes	Yes	No	62–64

* The lack of demonstrable effect may be due to studies not being powered to this end point.

** The pivotal study had to be prematurely terminated to evaluate the osteosarcoma risk.

Bisphosphonates can be administered orally or intravenously. The main advantage of intravenously administered bisphosphonates is that there are no adverse GI effects. The main adverse effect of intravenously administered bisphosphonate is the acute phase reaction which affects about 18% of bisphosphonate naïve patients, but only 9% of patients receiving their second annual infusion. The acute phase reaction is less commonly seen in patients receiving the monthly or weekly oral dose. The acute phase reaction manifests itself as fatigue, lethargy, generalized aches and pains and at times a low-grade temperature that may last a few days. It is not an allergic reaction. Severity can be reduced by acetaminophen or nonsteroidal anti-inflammatory compounds. Before the infusion patients should be encouraged to increase fluid intake. It might be prudent to avoid taking diuretics, especially loop diuretics, before and for a couple of hours after the infusion if feasible.

The absorption of oral bisphosphonates is very low: only 0.6%–3% of the orally administered dose is absorbed.[49] In order to maximize absorption the bisphosphonate has to be administered in the fasting state. It should not be taken with any fluid except with water. Some clinicians recommend it be taken with distilled water, which is free of additives that may interfere with the bioavailability of the orally administered bisphosphonates.

Side effects include heartburn, low abdominal pain, cramps, and sometimes diarrhea. The medication may irritate the small intestinal mucosa and induce peristaltic contractions, which can result in abdominal pain, cramps and/or diarrhea one to two hours after taking the medication. Symptomatic patients should eat a high-fiber food 30 minutes after taking the medication so that the food coats the unabsorbed bisphosphonate particles in the stomach.

Figure 44-2

Management of osteoporosis.

Bisphosphonates are excreted unchanged by the kidneys. Intravenously administered ones should not be administered if the creatinine clearance is lower than 35 mL/min and the dose of orally administered ones should be adjusted when prescribed to patients with impaired renal functions.

A formulation of risedronate (delayed release risedronate) can be administered non-fasting after breakfast. The active ingredient (risedronate) is surrounded by a chelating agent and the tablet is coated by a pH-sensitive layer unaffected by gastric acidity. Studies have documented comparable effects of this preparation to conventional risedronate.[48]

Arrhythmias, especially atrial fibrillation, have been associated with bisphosphonate therapy, particularly intravenously administered bisphosphonates. In most instances the onset of the arrhythmia is about a month after the IV administration making a cause and effect relationship unlikely.[50]

Rarely patients may develop ocular complications including scleritis and uveitis. These potentially serious conditions may occur weeks, months, or even years after initiating bisphosphonate therapy and should be treated as emergencies.[51] Nonspecific conjunctivitis and photophobia also have been reported. They are usually benign, self-limiting conditions, but need to be addressed as they may herald more serious complications.[52]

Skin reactions have rarely been reported with bisphosphonates including rash, pruritus, toxic epidermal necrolysis, and Stevens-Johnson syndrome.[53] Rare possible adverse events of bisphosphonates are discussed later, including atypical femoral shaft fractures and osteonecrosis of the jaw.

Osteo-anabolic medication

Teriparatide (recombinant human parathyroid hormone 1–34) is the only osteo-anabolic medication commercially available in the United States. Another compound, the entire PTH 1–84, also has been studied, but at the time of this book’s publication is not commercially available in the United States. Teriparatide stimulates bone formation and bone turnover, increases bone mineral density and reduces the risk of fractures.[62] It is administered for a maximum of two years. At the end of this course an antiresorptive agent should be administered to maintain the increases in BMD; if teriparatide is discontinued and no antiresorptives medication prescribed, the gains in BMD gradually fade away.[63] It is administered by daily subcutaneous injections. It is associated with relatively few adverse effects. An increased risk of osteosarcoma was noted in rats; this finding was not replicated in other experimental animals. Osteosarcoma rates in patients on teriparatide do not exceed the general population.[64] Contraindications to teriparatide therapy include hyperparathyroidism and radiation exposure.

Daily calcium intake

The recommended daily calcium intakes,[23] as well as the upper limit of intake as per the Institute of Medicine (IOM) are shown in Table 44-2.[65] It is preferable to get the recommended calcium intake from food as opposed to tablets. If calcium supplements and antacids must be taken, calcium citrate is preferred to calcium carbonate as the citrate compound does not need gastric acidity to be dissolved.

Many foods either contain calcium or are fortified with calcium. Calcium fortified orange juice for instance has the same content of calcium as milk (300 mg per 8 ounces). The food content of some select food is shown in Table 44-3. Drinking chocolate in particular could be rich in calcium. Readers are advised to check the food labels as different brands of the same product may contain different amounts of calcium.

Food labels often do not indicate the mg amount of calcium available in that particular food, but instead indicate the percentage of calcium. This percentage is based on the recommended daily intake of women between the ages of 19 and 50 years: 1,000 mg. For example, a label showing a serving contains 20% of the recommended daily calcium intake, means it contains 200 mg of calcium.

Vitamin D

Vitamin D is essential for the absorption of calcium through the intestinal mucosa. When there is adequate exposure to sunlight, it is formed in the skin: ultraviolet light converts 7-dehydro-cholesterol to cholecalciferol. Vitamin D can also be obtained from food: ergocalciferol from plant products and cholecalciferol from animal products. Vitamin D deficiency results in a negative calcium balance because of the decreased calcium absorption through the intestinal tract.

Vitamin D deficiency is common. As the skin ages it is less efficient at producing vitamin D, and dietary vitamin D intake is often low.

The diagnosis of hypovitaminosis D is established by assaying the serum 25-hydroxy-vitamin D level. There is no consensus on the optimum management of vitamin D deficiency. Common regimens include: cholecalciferol 4,000 units daily or ergocalciferol 50,000 units once a week for 12 weeks. Assaying the serum 25-hydroxy-vitamin D is recommended at the end of the 12-week course to determine whether the patient needs another course of vitamin D. Most patients respond to a 12-week course of vitamin D supplementation, but some need several courses to correct vitamin D deficiency.

A well-balanced nutritious diet

A well-balanced nutritious diet is important for a healthy skeleton.[66–68] Cognitively intact, physically independent older women living on their own are least likely to develop malnutrition: men living on their own are the most vulnerable population. However, women with cognitive dysfunction are susceptible to the development of malnutrition. Older people with dental problems often avoid difficult to chew protein-rich food. Poor dental health is a major cause of malnutrition in developed countries.

Sodium and caffeine intake

Excessive sodium and caffeine intake may lead to a negative calcium balance by increasing renal calcium excretion.[69] Sodium is ubiquitous in our diet; preserved and canned foods tend to be rich in sodium. Soda drinks contain sodium and may contain phosphoric acid which binds to calcium and interferes with its absorption.[70] But as long as the individual consumes the recommended calcium intake, she may safely consume three soda drinks or cups of coffee daily without jeopardizing her calcium homeostasis.

Cigarette smoking

Cigarette smoking increases the risk of osteoporosis and fractures.[71] A number of mechanisms are responsible including stimulation of osteoclastic activity and the lifestyle many smokers adopt including leading sedentary lifestyles and consuming a diet that is not well balanced and often deficient in protein, calcium, and vitamin D.

Alcohol abuse

Although alcohol intake in moderation tends to be associated with positive effects on skeletal health, regular consumption of two or more drinks a day has deleterious effects on the bone health through its effects on osteoblasts, osteoclasts, and osteocytes.[72–74] Regular excessive alcohol intake is also often associated with nutritional deficiencies, body composition changes, and a number of pathologies that increase the risk of falls and hence fractures.[72–74]

Physical exercise

There is ample evidence to show that a physically active lifestyle is associated with a healthier skeleton and that physical exercise at any age is associated with an increased bone mass and reduced risk of falls and possibly fractures.[75–77] Unfortunately most studies on exercise do not include fractures as end points. Bones respond best to a combination of endurance or aerobic exercises and resistive exercises.

Walking with light weights attached to each wrist and ankle is a useful physical exercise combining endurance and resistive exercises. In order to decrease the risk of injuring adjacent joints and fatigue, heavy weights should be avoided. Unfortunately the positive effects of exercise on bone mass last only as long as the individual exercises.

Atypical femoral shaft fractures

Concerns have been raised about a few patients on long-term antiresorptive therapy (bisphosphonate and denosumab) sustaining fragility fractures of the femoral shaft. The present evidence suggests these fractures are insufficiency fractures that have progressed and involve the entire cortex.[78] Although these fractures share many common features with osteoporotic fragility fractures, there are some basic differences between them. They are referred to as atypical femoral shaft fractures (AFSF) to differentiate them from the “typical” osteoporotic femoral shaft fractures.

Whereas typical osteoporotic fractures are usually comminuted, atypical fractures are noncomminuted and tend to be transverse or have a short oblique configuration. Atypical femoral shaft fractures are often preceded for several weeks by prodromal symptoms such as pain and tenderness along the femoral shaft.

It may be argued that by inhibiting bone turnover, antiresorptives may interfere with the healing of insufficiency fractures and therefore lead to a complete “atypical” fracture. A causal relationship between atypical fractures and antiresorptive therapy, however, could not be established especially given the large disproportion between the number of patients on antiresorptive therapy and the number of patients sustaining these fractures. Besides, some patients who sustained atypical fractures have not been on any antiresorptive medication. A review of pivotal studies could not document an increased incidence of these fractures in patients treated with antiresorptive medication.[79]

The risk of patients on bisphosphonates sustaining atypical femoral shaft fractures is low: 3–50 cases per 100,000 person-years.[78] Given the potential beneficial effects of antiresorptive medication, the rarity of atypical femoral shaft fractures, especially during the first three to five years of initiating treatment and given the frequent presence of prodromal symptoms that should alert patient and treating clinician of an impending fracture, health-care providers should not deny antiresorptive therapy to patients with osteoporosis. Patients and health-care providers, however, need to be vigilant.

Osteonecrosis of the jaw

There have been several reports of patients on antiresorptive therapy developing osteonecrosis of the jaw (ONJ).[80] Most of these instances developed in patients who underwent tooth extraction or invasive dental work. The majority of these patients were on bisphosphonates administered in large doses for malignant conditions, and many patients were simultaneously on other medications that may interfere with the healing process. Also, many patients had poor dental hygiene and were cigarette smokers.

A plausible link exists between antiresorptives and osteonecrosis of the jaw: antiresorptives decrease bone turnover to such an extent that injured or necrotic bone is not removed. But the sheer number of patients who have received antiresorptives medications and those who develop osteonecrosis of the jaw are such that it is not possible to establish a direct cause-and-effect relationship. At most antiresorptive therapy may contribute to the development or worsening of the condition.

Four different stages of ONJ have been described: in stage I a cavity with bone tissue at its base is visible, but it is largely asymptomatic. In stage II the lesion is painful and there are signs of inflammation. In stage III fistulae and purulent discharges are seen. A stage 0 has been added to describe patients who experience jaw pain, have some of radiological features of ONJ, and have been on antiresorptive medication.[81]

The essence of management is scrupulous oral hygiene and frequent use of oral antiseptics. Eventually most stage I cases of ONJ heal spontaneously. Rarely surgical intervention by a specialist with experience managing ONJ is needed. The fear of ONJ should not deter clinicians from prescribing antiresorptives. The risk-benefit ratio is very much in favor of taking the antiresorptives medication.