Bone and joint supplements can help America’s gears run smoothly again.

In March 2002, President George W. Bush signed a proclamation declaring that the U.S. National Bone and Joint Decade would begin. The initiative’s intent was to raise awareness, promote the prevention of musculoskeletal diseases and advance research that would lead to improvements in prevention, diagnosis and treatment. But as this decade is drawing to a close, is America feeling any better?

Well, despite catchy campaigns such as “Got Milk?,” approximately one in two Americans over the age of 18 and many children are restricted by a musculoskeletal disorder such as arthritis, back pain, osteoporosis or other injury (1). In 2004, the estimated total cost of treatment and lost wages associated with musculoskeletal diseases in the United States alone was $849 billion, equal to 7.7% of the gross domestic product (1).

And, judging by a recent article listing Vicodin (a branded combination of the narcotic oxycodone and acetaminophen) as the number one prescribed medication in the United States (2), it seems we have a long way to go. This medication is dangerously overprescribed for chronic pain, much of which can be attributed to bone and joint pain, despite a recent FDA recommendation to ban the drug entirely. When taken excessively, this drug can lead to dependency and liver damage. Other non-steroidal anti-inflammatory drugs (NSAIDs) are also very commonplace, but can lead to gastrointestinal distress, increased blood pressure and increased risk of cardiovascular disease.

To avoid continuing its painful walk down this potentially destructive path, America needs to take better preventative care of its bones and joints. It seems milk alone may not be pulling its weight, so…got supplements?

A Flexible Market
The natural products market has a lot to offer in terms of bone and joint health aids, and is continuing to grow, but changes in consumer attitudes are beginning to shift the market.

Keeping a firm grip. Glucosamine and chondroitin have been leaders in the bone and joint category for years because they have been found to “significantly decrease” knee pain for people suffering from moderate-to-severe osteoarthritis (3). But, they also have been increasingly scrutinized over their efficacy, leading some to wonder if their reign over this supplement category is coming to an end. This is unlikely, but the category is certainly evolving.

Concerns about country of origin, traceability and local sourcing as well as animal rights and even allergies have spurred some changes. Lakshmi Prakash, Ph.D., president of innovation and business development at Sabinsa Corporation, East Windsor, NJ, says, “Quality issues with glucosamine and chondroitin, and fragmented supply chain management systems in the principle raw material markets have come into focus (e.g., crustacean shells and bovine sources for glucosamine and chondroitin respectively could be mixed with material from other animal sources; heavy metal and other contaminant residues may be high).” As a result, a new trend is to now utilize corn-derived vegetarian/vegan glucosamine rather than using Chinese-source shellfish.

The collagen market, too, is starting to see some changes. Holista Colltech, based in Wembley, Australia, manufactures collagen from sheep, which, according to the company’s CEO, Dato’ Dr. Rajen M., “is unique in that it is mammalian and free of cultural and religious issues.” Bovine collagen, for example, has faced issues related to cultural sensitivities and transmissible spongiform encephalopathies diseases (TSE) (i.e., “mad cow”), while shark collagen is very difficult to trace. According to Rajen, ovine (not to be confused with bovine) is fully traceable from sheep with no TSE diseases.
Retailers should be aware of the sources of bone and joint supplements so they can effectively help their customers choose which is most appropriate for them. For a cheat sheet of the sources for the most commonly used bone/joint supplements, see the sidebar “Cheat Sheet: Where Do Bone/Joint Supplements Come from?”

Cheat Sheet: Where Do Bone/Joint Supplements Come from?

Neil E. Levin, CCN, DANLA, nutrition education manager at NOW Foods, Bloomingdale, IL lists the sources of the most common bone/joint supplements:

Glucosamine:    Most glucosamine formulas use shellfish-derived material, though a few have vegan-friendly fermented sources.

Chondroitin Sulfate:     Only available from animal sources at this time, particularly from cattle.

Collagen:     Available as an animal-derived product (cows, pigs, chickens, sheep, sharks). Limited availability in plant varieties.

Hyaluronic Acid (HA):    HA can be either animal or plant sourced but the best source (based on molecular weight) seems to be the fermented material that is vegan.

MSM:     A vegan source of biological sulfur in the form that the body prefers for tissue maintenance and repair.

Microcrystalline Hydroxyapatite Complex (also known as Calcium Hydroxyapatite, MCHA or MCHC):    A beef-based bone matrix, providing much more than just calcium for bone health.

Coral Calcium:     Derived from coral, a sea animal, though from mined deposits rather than live animals. There is also an algae-based source of calcium, magnesium and trace minerals.

Vitamin K:    A vegan material, but is often sold in beef gelatin capsules, so vegetarians have to read labels closely.

Vitamin D:    Available in two main forms available as dietary supplements: D3 (cholecalciferol from animal sterols derived from sheep lanolin) and D2 (ergocalciferol from plant sterols derived from yeast). While some science seems to show that D3 is the preferred form, recent science has actually shown that the distinction between these forms disappears with daily usage, such as supplementation or food fortification, over a long period of time.

Because shoppers are more concerned with ingredient sources, plant-based supplements are seeing growth. However, retailers should be sure that any stocked veggie glucosamine products are derived from non-GMO corn.

Dean Mosca, president of Proprietary Nutritionals, Inc., Kearny, NJ, confirms that the vegetarian bone and joint market is indeed growing and can provide benefits that are just as effective as those found in animal products. Celadrin, the company’s proprietary blend of esterified fatty acids (originally made from beef tallow), is also available as Vege Celadrin, which is made from palm oil, palm kernel oil, olive oil, nutmeg coconut oil and unsaturated vegetable oils. According to Mosca, the plant-sourced material provides the same fatty acid composition that was proven effective in the original product.

In addition to their effectiveness, vegetarian formulations are also sought after for their earth-friendly benefits, Prakash adds, “In plant-based extracts, green practices and sustainability are increasingly in focus—the environment-conscious consumer is willing to pay a higher price for a ‘green’ product derived from sustainable resources.”

Sustainability is at the heart of many products, including patented eggshell membrane and eggshell calcium products (JOINTHealth and BONEHealth from Membrell). According to Micah Osborne, president of Carthage, MO-based Membrell, “Both product lines use ingredients sourced from sustainable eggshells that normally would have been discarded but are now used as essential nutrients.” He adds that the ingredients can be traced all the way back to the farm from where the egg came. The patented natural eggshell membrane ingredient is composed of naturally occurring glycosaminoglycans including chondroitin and hyaluronic acid, plus collagen and other proteins for proper joint health and flexibility. Two clinical trials on the effects of eggshell membrane show that a single 500-mg dose per day can reduce pain and increase flexibility in just 10 days (5, 6).

No stretch of the imagination needed. Research in the bone and joint health category abounds, providing continual scientific support that natural products can be effective. Even old standards like glucosamine and chondroitin are still being heavily studied. The two are traditionally recommended together, often with methylsulfonylmethane (MSM) as well, but there has been more exploration about combining other ingredients that yield significant results, most notably, omegas. For example, a recent study published in Advances in Therapy reported that combining omega-3 fatty acids with glucosamine might be more effective than using glucosamine alone. The clinical trial is said to be the first of its kind to utilize glucosamine and omega-3 fatty acids in people suffering from osteoarthritis and showed that 1,000 mg of EPA and DHA from fish oil, and 1,500 mg of glucosamine reduced morning stiffness and pain in hips and knees by the end of the study (7).

Unique sources of omegas have also been in the limelight. For example, omega-rich extracts from New Zealand green-lipped mussel (Perna Canaliculus), showed significant benefits in 80% of study participants with osteoarthritis of the hip and knee after eight weeks of supplementation (8).

Other ingredients, such as pine bark extract, continue to be researched as well. A branded pine bark extract ingredient (Pycnogenol from Horphag Research, distributed by Natural Health Science, Hoboken, NJ) has been investigated for its ability to inhibit the cyclooxygenase enzymes, (COX-1 and COX-2), which are key elements of inflammatory response. Thirty minutes after 10 volunteers received 300 mg of the extract, the mean inhibition of COX-1 and COX-2 was 22.5 and 15%. (9). A more recent study published in International Immunopharmacology found the extract inhibited the pro-inflammatory lipoxygenase (5-LOX) enzyme in addition to COX-2 (10).

Joosang Park, Ph.D., vice president of scientific affairs for BioCell Technology, Newport Beach, CA, notes that wasabi (Wasabi japonica) is a relatively new player in the joint supplement category. According to Park, i-Sabi, the branded wasabi ingredient from BioCell, not only demonstrates unique properties as a cell-permeable antioxidant, but also as a selective COX-2 inhibitor to address inflammation and oxidative stress.

Step By Step
With so many products and ingredients available, it is important to be familiar with formulation and dosing to yield the greatest benefits. To help differentiate what individual customers may need, retailers might divide the category into three sections based on our needs as we age: foundation (kids), prevention/maintenance (teens/adults) and therapeutic (seniors).

Kaori Shimazaki, Ph.D., technical specialist for Jarrow Formulas, Los Angeles, CA, says, “During childhood and young adulthood, recommended dosages may go up due to increased body mass and activity levels. As one gets older, the recommended dosage may further increase due to reduced nutrient absorption, slowed metabolism and other physiological changes that weaken the normal growth and repairing processes.”
Jordan Rubin, CEO and founder of Garden of Life, West Palm Beach, FL, agrees. “While people of all ages can benefit from vitamins, minerals and systemic enzymes and essential fatty acids, individuals most interested in joint and bone health formulations are the aging population who long to remain active and recapture their youth. The need for minerals such as calcium, fat-soluble vitamins such as D and K, and potentially decreasing store of enzymes make the need for bone building and joint-supporting supplements greater as we age,” he says.

Right on time. As we age, stomach acids and digestive enzymes decrease, thereby limiting our ability to absorb nutrients, but absorption is always an important issue. Dosage timing can be essential for optimal absorption. For example, says Trisha Sugarek, national educator and research and development specialist for Bluebonnet Nutrition Corp., Sugar Land, TX, “It is well known that only 400–600 mg of elemental calcium can be absorbed at one time by the gastrointestinal tract.” Therefore, spaced out doses can help ensure greater absorption.

“In general, bone and joint supplements can be taken with meals and are best spread out during the day to maximize absorption. More specifically, all fat-soluble nutrients should always be taken with fat-containing meals; these include vitamins A, D, E, and K, as well as CoQ10, lutein, lycopene, alpha lipoic acid, etc.,” adds Neil E. Levin, CCN, DANLA, nutrition education manager at NOW Foods, Bloomingdale, IL. Take fish oil supplements with meals to enhance nutrient absorption, suggests Stuart Tomc, CNHP, national educator at Nordic Naturals, Watsonville, CA.

Different kinds of calciums, too, are best taken at specific times. Chelated calciums (predigested forms like citrates, malates, amino acid chelates, ascorbates, etc.) have a more neutral pH and can be taken at any time. Crude forms like calcium carbonate, dolomite and coral calcium are very alkaline and require good stomach acid to properly digest. “The crude forms also benefit from taking them with meals, as the minerals freed from their original matrixes typically recombine with acids in the foods to create compounds that are quite similar or even identical to the chelated forms…sort of a do-it-yourself mineral chelate kit,” advises Levin. For more on calcium absorption, see “Metabolism, Efficacy and Safety of the Primary Bone Minerals Calcium and Strontium.

The time of day also can make a difference. Ken Whitman, president of Peter Gillham’s Natural Vitality, Burbank, CA, says, “Bone building peaks between 10 pm and 4 am. That is why you should take bone building supplements 4–5 hours before bedtime.”natural health science

This may also have other advantages, says Levin, who notes that some people seem to benefit by taking calcium and/or magnesium in the evening to aid in relaxing and going to sleep.

Formulation can also be a key aspect of timing supplement doses. “Sustained-release actives are preferred so that the benefits persist over a 8–12-hour period (2–3 daily doses). Therefore, the benefits of a dose taken at night before resting would persist in the early morning hours on waking, when the symptoms of inflammation are most pronounced,” says Prakash.

Bioavailability beckons. The benefits of a sustained-release formulation are particularly relevant to the bioavailability of glucosamine because the acid environment of the gut leads to substantial loss in the gastrointestinal tract. Additionally, says Prakash, “Sustained-release formulations also help to establish and maintain blood levels of natural actives of plant origin, with a short pharmacokinetic half life.”

The gastrointestinal environment also poses a risk for the delivery of curcumin, which has been noted for its anti-inflammatory benefits for joint health. The mechanistic rationale behind curcumin’s effectiveness is that it blocks transcription factors involved in inflammation (AP-1/NF-kB/STAT3) and it quenches reactive oxygen species. However, a higher pH causes it to degrade faster, making the digestive system a precarious place for curcumin. Because curcumin is hydrolytically unstable at intestinal pH, it has extremely poor oral bioavailability. Human ingestion of 12 g of curcumin alone produced a maximum serum concentration of only 51 ng/ml (11).

There are ingredients, however, that are formulated to increase the bioavailability and effectiveness of curcumin. BioPerine from Sabinsa (also found in the company’s Curcumin C3 Complex) significantly increased serum rates of curcumin in a human clinical trial (12).

Also, curcumin strongly interacts with phospholipids, which can help protect curcumin from intestinal hydrolysis and promote absorption into cells. One bioavailable curcumin product (Meriva from Indena) utilizes phospholipids for curcumin’s easy absorption and stability. membrell

Another avenue of bioavailability research pursues agave fructans for bone health. It is thought that these non-digestible carbohydrates may support the growth of beneficial bacteria in the intestine, leading to better absorption and retention of important minerals such as calcium and magnesium. In a mouse study, calcium levels in plasma and bone were increased (53.1 to 56-85 mg/ml and 0.402 to 0.474-0.478 g/g bone respectively) and osteocalcin levels increased (>50%), suggesting that supplementing the standard diet with agave may prevent bone loss and improve bone formation (13).

Out of Joint
Here is a breakdown of three common bone and joint conditions that leave Americans in pain everyday:
Osteoporosis is related to the deterioration of bone metabolism that is common with increasing age. It is common in post-menopausal women because of decreased estrogen. However, says Marci Clow, RD, senior director of product research for Rainbow Light Nutritional Systems, Santa Cruz, CA, the differences between women’s and men’s bone health are minimal. She says, “Throughout all stages of life, men have the same calcium requirements as women: 8 mg for ages 4–8; 1,300 mg for ages 9–18; 1,000 mg for ages 19–50; and 1,200 mg for over age 50.” She adds that men may tend to get slightly higher levels of calcium because they generally eat higher amounts of food to start with.

Select Product Offerings

BioCell Technology: BioCell Collagen II, i-Sabi and Estraflex CMO.

Bioforce USA: Arnica Rub.

Bluebonnet Nutrition Corp.: Liquid Calcium Magnesium Citrate, Osteo-Bone Formula Vcaps, Caplcium Citrate Magnesium plus Vitamin D3 Caplets, Turmeric Root Extracts Vcaps, Glucosamine Chondroitin Plus MSM Vcaps, Glucosamine Celadrin MSM Vcaps, GSX Formula Vcaps, Cherry Fruit Extract Vcaps, Trimology LFO Vegetarian Softgels and Natural Omega-3 Joint Formula.

BSP Pharma: FlexNow.

Country Life Vitamins: Bone Solid.

Garden of Life: The Grow Bone System includes Vitamin Code Raw Calcium formulated with AlgaeCal Raw Clinical Strength and Vitamin Code Growth Factor S; Wobenzym N; FYI and FYI Ultra.

Holista Colltech, Ltd.: OVICOLL , Bonex Gold, MOO tablets and Nacox.

Jarrow Formulas: Vegetarian/Vegan Bone-Up, Bone-Up, Ultra Bone-Up, JarroSil Activated Silicon, SAM-e, Ultra Joint Builder, CalMag, Sensoril Ashwgandha extract, bromelain, Curcumin 95, Glucosamine HCI, hyaluronic acid, MSM-Sulfur, Hi-Lignan Flax Seed Oil and Yucca 4:1 Extract.

Membrell, LLC: BONEHealth, JOINTHealth plus Anitoxidants and JOINTHealth.

Natural Health Science (NHS): Pycnogenol.

Nordic Naturals: Omega Joint and Omega Joint Xtra (includes UC-II Natural Collagen Concentrate).

NOW Foods: Bone Strength, Bone Calcium. Calcium Citrate Caps, Calcium & Magnesium Softgels, Liquid Cal-Mag and a variety of other Bone Support formulas. Joint Support, Extra Strength Glucosamine/Chondroitin, Red Mineral Algae with Aquamin, Ache Action with Decursinol and Aquamin, D-Flame COX-2 and 5-LOX enzyme inhibitor, Flex Mobility Vcaps or Liquid with Flavanflex and Regenasure vegetarian glucosamine, UC-II Undenatured Type II Collagen, Turmeric and Bromelain Vcaps, and Serrazimes for systemic enzymatic effects.

Peter Gillham’s Natural Vitality: Osteo Calm.

Proprietary Nutritonals, Inc. (PNI): Perluxan, Celadrin, Vege Celadrin.

Rainbow Light Nutritonal Systems: OsteoBuild, Calcium Citrate Mini-Tabs, Food-Based Calcium, Vitamin D 400 IU and 1,000 IU Sunny Gummies, RejuvenAge 40+ Multivitamin, and Women’s Nutritional System.

Sabinsa Corp.: Curcuma C3 Complex, Boswellin PS, Polysal, Acticissus, Arthriblend SR, NiLitis SR.

Soft Gel Technologies, Inc.: Perluxan soft gels, EZmega 3.

So for everyone, says, Sugarek, “It is vital to the body in the midst of aging and hormonal imbalances that the pharmacological and nutritional factors are taken into account to prevent age-related bone loss, which leads to an increased risk in fractures of the hips, wrists and spine.”

Although the latest and greatest product may seem like the best idea, Jason Mitchell, vice president of research and product development and education for Country Life Vitamins, Hauppauge, NY, warns against this. He says, “Dietary supplements materials are not like computers that become outdated and obsolete. New is not always better…especially in the area of calcium.” Mitchell notes that a particular form of calcium called MCHA (microcrystalline hydroxyapetite) also provides collagen and phosphorus, vital elements for bone structure and function, emphasizing that 90% of the body’s calcium is stored in the form of calcium phosphate. Taking supplements properly, rather than jumping at the newest product will be more helpful. Mitchell recommends recommending that for every 1,000 mg of supplemental calcium taken, the body requires an additional 500 mg of phosphorus.

Whitman says that his company utilizes ionic minerals in a balanced ratio for the best assimilation. Other nutrients that support bone health are manganese, boron, zinc and copper.

Osteoarthritis (OA) is when low-grade inflammation results in joint pain caused by the destruction of cartilage that acts as a cushion inside joints and a decrease in the synovial fluid that lubricates those joints. This condition can make mobility limited and painful. Sugarek says, “By employing the right nutrients, the body will be able to repair and maintain cells and tissues for optimal joint health and collagen synthesis that is also required for bone support.”

The common answer for dealing with OA pain has been NSAID prescriptions, but one study found 1,200 mg of S-Adenosylmethionine (SAMe) to be helpful for the management of osteoarthritis pain, and demonstrates similar effectiveness to a popular COX-2 inhibitor, celecoxib (200 mg Celebrex) (14).

Rheumatoid arthritis is a progressive autoimmune condition characterized by chronic inflammation leading to the destruction of the cartilage, bone and ligaments, causing joint deformity. Omega-3 supplementation can help reduce inflammatory response, particularly fish oil.

Because of the prevalence of these conditions in the United States, a trend of condition-specific products seems to be growing (i.e., “bone health product” rather than “calcium product”). In addition to ingested supplements, topical remedies may be of some use, such those that contain arnica (Arnica montana). Eileen Sheets, managing director at Bioforce USA, Ghent, NY, says, “The active ingredients in arnica have been demonstrated to exert significant anti-inflammatory activity, which may be useful for helping to reduce edema.” Other notable herbal anti-inflammatory supplements include boswellia serrata, devil’s claw and horsetail extract.

Bones of Contention
Some may wonder why bone and joint supplements are often lumped together. Physiologically, there are similarities: the degradation of both bones and joints can lead to conditions like osteoporosis and osteoarthritis. Another reason is that both categories share certain compounds that make up the musculoskeletal system. “One of the nutrients that would benefit both tissues is silicon. This element can stimulate the production of collagen, which is the main fibrous structural protein of fascia, cartilage, ligaments, tendons and bone,” says Shimazaki. Non-mineral components such as collagen and proteoglycans make up about 27% of bone mass, she adds, contributing to bone quality by affecting factors such as bone density, flexibility and rebuilding.

According to Sugarek, “Collagen provides the structural foundation for bones, joints, ligaments and cartilage, which is the reason why bone and joint health overlap and the elements, such as glucosamine, MSM, vitamin C and chondroitin for their health benefits, are shared.”

Category conundrums. Some manufacturers have begun to differentiate more clearly between bone and joint health. For example, Rubin says, “When categorizing formulations, I do believe that while certain nutrients and compounds provide both bone and joint supportive benefits, the most effective formulas are directed more specifically at bone health or joint health. The challenge of combination formulas is not receiving the clinically effective dosage for relevant nutrients and compounds.”

Beverly Yates, N.D., medical advisor to BSP Pharma, Egg Harbor Twp., NJ, agrees: “One can make a case for separating these two categories. Bringing them together blurs the difference between supporting the need for improved structural integrity in bone, making it stronger; and the need to reduce pain and discomfort, and restore lost bone and remodel damaged cartilage.”

Therefore, some companies have made this distinction in their product offerings, focusing on how the product will function for the consumer. For example, Levin says, “NOW actually separates its joint support category into two distinct sections: Joint Structural Support Products and Joint Pain & Mobility Products. This suggests to the customer that they need ‘one from column A and one from column B.’ By directing their thought process to the two main functional solutions that consumers seek, and by providing those products in both categories as well as overlapping combination products, we can supply a more holistic and sustainable nutritional joint support program.”

For people who have already sustained severe joint damage, such as those with rheumatoid arthritis, pain-specific products speak to their needs. Also, Kevin J. Ruff, Ph.D., MBA, director of scientific and regulatory affairs for Membrell says, “The biggest thing for people with severe joint damage is to stop the damage from progressing and to manage the pain associated with the existing damage.” Cartilage is quite slow to regenerate, he says, but it can happen if people give it the best chance through lifestyle changes, such as a more healthy diet, regular exercise, and joint health supplements.

Taking combinations to heart. In the past few years, the correlation between bone health and cardiovascular health has been increasingly pursued because inflammation is believed to be a root cause of disease conditions in both categories. Thus, it stands to reason that anti-catabolic, anti-inflammatory supplements could successfully address bone and joint health in addition to cardiovascular health.

Sugarek says, “This correlation was founded on the observation that women who have coronary heart disease have more osteoporosis, and women who have osteoporosis are more likely to have coronary heart disease. In fact, they share common features—both are age related, both are rare before the age of 30 and both are very common after the ‘change of life’ occurs in women because estrogen is considered protective for both heart and bone health.”

However, the connection goes much deeper, to the cellular level, as both heart and bone/joint health depend on similar nutrients such as vitamin D3, K2 and magnesium. Whitman says, “One common denominator of heart health and bone health is the daily need for magnesium and balancing calcium intake with sufficient magnesium. We believe a 1:1 ratio is best because it reflects the balance at a cellular level, which is where these minerals have their greatest impact.”

Shimazaki says, “Vitamins D and K cannot only stimulate the synthesis and activity of osteocalcin, a bone protein important for bone absorption and bone mineralization, but can also prevent calcification in the soft tissues, including blood vessels by eliminated unnecessary calcium deposits.” By preventing atherosclerotic plaque development and keeping calcium in bones where it belongs, blood pressure—and overall cardiovascular health—can improve.

Omega-3s also are beneficial for bone, joint and heart health. Diets rich in omega-3 can reverse the pro-inflammatory effects of omega-6 in the body, resulting in a reduction of bone breakdown caused by these pro-inflammatory agents, as well as staving off blood platelet aggregation and lowering triglycerides, cholesterol and blood pressure.

Because of the connection between these crucial nutrients, we are starting to see more products with them all included. Also, experts forecast that combination products marketed for bone and heart health will be a growing trend (15). Ruff says, “Diseases that have similar etiologies are great candidates for combination products.”

For example, Brandon Nomura, territory manager at Soft Gel Technologies, Inc., Los Angeles, CA, notes, “When a product sabinsacan combine health claims for more than one category, the consumer sees an ‘added benefit’ to their supplements and may feel they’re getting more value for their money, as well as allowing them to possibly take less individual supplements. No one wants to have to swallow a handful of pills every day!”

Mitchell agrees. “The more we find that conditions happen in tandem, the more it makes sense that combination formulas be provided,” he says. “I’m not saying we should simply start combining everything, but when it makes sense scientifically, we should address that there are ways to address more than one thing at a time.” WF

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Published in WholeFoods Magazine, July 2010 (published online ahead of print, June 18, 2010)