Calcium and D supplementation in osteoporosis

Osteoporosis may be a disorder of bone characterized by reduced mineral density and bone mass. Multiple therapeutic regimens are designed to forestall or treat bone loss in postmenopausal women and also the elderly. the primary step within the prevention or treatment of osteoporosis is ensuring adequate nutrition, particularly maintaining an adequate intake of calcium and cholecarciferol. Adequate calcium and ergocalciferol nutrition is vital in people of all ages, especially in children and therefore the elderly within the latter group, as an example, the administration of calcium and viosterol reduces the speed of bone loss and will decrease fracture risk during this same population, calcium and D supplementation also reduces tooth loss Calcium and calciferol supplementation within the treatment of osteoporosis are reviewed here. Detailed information regarding pharmacologic therapy for osteoporosis and also the role of calcium within the pathogenesis of osteoporosis is discussed separately.

 EFFICACY

— Calcium and vitamin D are necessary for normal skeletal homeostasis. D enhances intestinal absorption of calcium. Low concentrations of D are related to impaired calcium absorption, a negative calcium balance, and a compensatory rise in internal secretion, which ends in excessive bone resorption.

Careful calcium balance studies have shown that calcium balance is said to calcium intake; the less calcium one takes in, the more negative the calcium balance. this will be reversed by increasing calcium intake and maintaining adequate fat-soluble vitamin stores. In general, calcium balance becomes positive at a mean calcium intake of 1000 mg/day in premenopausal women and 1500 mg/day in postmenopausal women who don’t take estrogen The importance of adequate calcium and viosterol intake for skeletal health is supported by several observational studies and by randomized trial data. Observational data — Many studies have shown an inverse relationship between serum concentrations of 25-hydroxyvitamin D (25OHD) and hormone (PTH) The maximal suppression of PTH by vitamin D is one criterion by which the optimal serum 25OHD concentration is defined. Estimates vary widely but range from 20 to 40 ng/mL (50 to 100 nmol/L) Other experts support the thesis that suppression of PTH by 25OHD follows a continuum across a large range of viosterol concentrations, and levels above 20 ng/mL are capable suppress PTH, assuming normal renal function The compensatory rise in hormone, which occurs within the setting of low calciferol, leads to excessive bone resorption. Many studies, including an outsized population-based study (NHANES-III) that included 13,432 participants, have shown a positive association between serum 25OHD and bone mineral density additionally, in an exceedingly prospective cohort study of 1279 community-dwelling older men, those with 25OHD <20 ng/mL (50 nmol/L) had significantly higher rates of hip bone loss over time (approximately 0.5 compared with 0.3 percent/year in men with serum 25OHD >20 ng/mL In several but not all observational studies, lower serum concentrations of 25-hydroxyvitamin D (25OHD, calcidiol) were related to the next risk of hip fracture. In one in every of the most important of those studies, 400 women with hip fracture were compared with 400 matched controls and followed for seven years The mean serum 25OHD concentrations measured at study entry were significantly lower in patients who subsequently had a hip fracture (22 versus 24 ng/mL [56 versus 60 nmol/L]) The increased risk of hip fracture was most apparent in women with very cheap serum 25OHD concentrations (OR 1.7, 95% CI 1.0-2.8 for girls in quartile one [<19 ng/mL (47.5 nmol/L)]) compared with women in quartile four (>28 ng/mL [70.7 nmol/L]). Similar findings were reported in men (hazard ratio 2.36, 95% CI 1.08-5.15 for men within the lowest versus highest quartile of total 25OHD) additionally to hip fracture, serum 25OHD concentrations below 20 ng/mL (30 nmol/L) are related to the next risk of other osteoporotic fractures, including vertebral, wrist, and proximal humerus fractures in a very prospective cohort study of elderly Swedish men (mean age 71 years), serum 25OHD levels below 16 ng/mL (40 nmol/L) were related to a modestly increased risk for fracture (HR 1.65, 95% CI 1.09-2.49 within the aggregate, these observations suggest that calcium and D supplementation could protect bone by preventing bone loss and by healing subclinical osteomalacia. Although the optimal serum 25OHD concentration to keep up skeletal health isn’t firmly established, serum values exceeding 19 to 24 ng/mL (47.5 to 60 nmol/L) are supported by observational studies Randomized trial data — Evidence supporting the advantage of calcium and D supplementation in patients with osteoporosis comes largely from prospective, randomized, placebo-controlled trials Although variety of trials have reported a beneficial effect of calcium or calcium plus cholecarciferol on bone density in postmenopausal women and older men the information on fracture rates are more variable Some trials have reported a discount in fracture but large randomized trials haven’t shown any reduction in fracture risk with calcium plus viosterol In the most important of those trials (Women’s Health Initiative), however, subgroup analysis revealed that calcium and calciferol supplementation was related to reduced fracture incidence in those subjects who were most compliant The Women’s Health Initiative trial randomly assigned 36,282 postmenopausal women ages 50 to 69 years (not selected for low bone density or osteoporosis) to calcium (1000 mg/day) plus D (400 int. units/day) or placebo (personal supplementation of up to 1000 mg additional calcium and 600 units fat-soluble vitamin was also allowed, as was bisphosphonate, calcitonin, and hormone therapy use [over one-half of subjects were taking hormone therapy the subsequent results were seen: • After a mean follow-up period of seven years in a very subset of girls who had bone mass measurements performed, hip bone mineral density was 1.06 percent higher within the calcium-vitamin D group compared with the placebo group.

• The risk of hip fracture with calcium-vitamin D (intention-to-treat analysis) was not up to placebo although this wasn’t statistically significant (HR 0.88, 95% CI 0.72-1.08). However, when only compliant subjects were analyzed (predefined as people who took over 80 percent of medication), a big decrease in hip fracture was seen (HR 0.71, 95% 0.52-0.97).

• In all subjects, the danger of kidney stones was increased with calcium-vitamin D supplementation (HR 1.17. 95% CI 1.02-1.34). The trial had variety of limitations: a greater fracture reduction may need been seen if subjects had been selected on the premise of low bone density or low calcium/vitamin D intake at baseline. additionally, the high percentage of ladies taking hormone therapy may have made it difficult to determine an impression of the calcium-vitamin D on bone, and lastly, the ergocalciferol supplementation may are too low

Calcium versus D

— In many of those trials, it’s difficult to differentiate the effect of calcium from that of viosterol. Randomized trials of calcium only or cholecarciferol only have shown mixed results, likely because of differences in patient populations and study design. A meta-analysis of 5 trials comparing fat-soluble vitamin (400 to 1370 units/day) with placebo in over 14,500 elderly men and ladies reported that cholecarciferol supplementation alone failed to reduce fracture risk (RR 1.03, 95% CI 0.84-1.26) within the same review, a separate meta-analysis of 11 trials comparing calcium (500 to 1200 mg/d) plus cholecarciferol (300 to 1100 units/day) with placebo showed that combined supplementation reduced the danger for total fractures (RR 0.88, 95% CI 0.78-0.99 in a very subgroup analysis, the danger reduction was larger among institutionalized elderly than community dwelling individuals (RR 0.71 versus 0.89) Other meta-analyses of trials comparing calcium, vitamin D, or both with placebo or no treatment reported a beneficial reduction in fracture with calcium and calcium plus ergocalciferol but not with D alone Relative risk reductions for hip fracture ranged from 0.81 to 0.87 for combined calcium plus D supplementation These findings suggest that supplementation with both calcium and calciferol reduces the danger of fracture.

 OPTIMAL INTAKE

— The optimal dose of calcium and vitamin D is uncertain. during a number of trials that reported a beneficial effect of calcium on bone density in postmenopausal women and older men, calcium supplement doses ranged from 500 to 1200 mg daily Baseline calcium from diet varied from approximately 600 to 1000 mg daily. Thus, total (diet plus supplement) calcium intake ranged from approximately 1100 to 2000 mg daily. a good range of ergocalciferol doses were utilized in the clinical trials. a number of the trials were designed to review intermittent dosing of viosterol, specifically 100,000 units administered every three to four months whereas others used 400 units of cholecarciferol daily One meta-analysis of randomized trials didn’t show differential effects on fracture risk reduction based upon the dose of viosterol However, another analysis showed a big effect of vitamin D dose when the particular fat-soluble vitamin intake (rather than assigned fat-soluble vitamin dose) was calculated during this pooled analysis of patient level data from 11 randomized trials (31,022 persons, mean age 76 years) of oral viosterol supplementation, with or without calcium, compared with placebo or calcium alone, there was a major reduction in incidence of hip (RR 0.70, 95% CI

0.58-0.86) and nonvertebral (RR 0.86, 95% CI 0.76-0.96) fracture within the individuals with the very best calculated actual vitamin D intake (median 800 units daily, range 792 to 2000 units daily) compared with controls. There was no reduction in risk of hip fracture at actual intake levels but 792 units daily. only a few of the trials included within the meta-analysis provided information on baseline and follow-up serum 25-hydroxyvitamin D levels and, therefore, the optimal serum 25-hydroxyvitamin D concentration for fracture prevention couldn’t be established. In two placebo-controlled trials of high-dose (300,000 to 500,000 units) viosterol administered once yearly (without calcium supplementation), vitamin D didn’t reduce the chance of fracture In one in all the trials, the chance of falls and fracture was increased within the fat-soluble vitamin group (RRs 1.15, 95% CI 1.02-1.30 and 1.26, 95% CI 1.00-1.59 for falls and fracture, respectively) within the ergocalciferol group, the median 25OHD concentrations after one and three months were approximately 48 and 36 ng/mL (120 and 90 nmol/L), respectively. Based upon the meta-analyses discussed above, we recommend 1200 mg of calcium (total of diet and supplement) and 800 int. units of fat-soluble vitamin daily for many postmenopausal women with osteoporosis. Although the optimal intake (diet plus supplement) has not been clearly established in premenopausal women or in men with osteoporosis, 1000 mg of calcium (total of diet and supplement) and 400 to 600 int. units of vitamin D daily are generally suggested. We recommend not administering yearly high-dose (eg, 500,000 units) D. These recommendations are in step with the Institute of drugs Dietary Reference Intakes for calcium and vitamin Certain coexisting medical problems may alter these requirements. In patients at very high risk for fracture in whom there’s a clinical suspicion that the standard doses are inadequate (malabsorption, decreasing bone mass), measurement of 25OHD concentrations could also be necessary to make sure that supplementation is adequate. Commercial assays measure total 25OHD, but some labs report vitamin D2 (25OHD2) and D3 (25OHD3) values separately. The optimal serum concentration refers to the combined total. The optimal serum 25OHD concentration for skeletal health is controversial. The Institute of drugs supports 25OHD concentrations above 20 ng/mL (50 nmol/L) but not chronically exceeding 50 ng/mL (125 nmol/L) the next serum concentration could also be necessary for skeletal benefits, particularly in older individuals at greater risk. Thus, some patients require quite 800 units daily to take care of serum levels of 30 to 40 ng/mL (75 to 100 nmol/L Optimal serum 25OHD concentrations are discussed in additional detail elsewhere. Optimal intake may be achieved with a mixture of diet plus supplements. Calcium appears to be also absorbed from supplements as from milk and supplements were employed in the above trials demonstrating get pleasure from increased calcium intake. it’s likely, therefore, that supplements aren’t less effective than calcium found naturally in dairy products. it’s important for patients to remember that calcium and calciferol alone are probably insufficient to forestall bone loss although they’ll be beneficial in some subgroups (the elderly, those with low intake at baseline). ergocalciferol supplementation is important for variety of other reasons independent of bone health; these are reviewed separately .

DIETARY SOURCES Calcium

— A rough method of estimating dietary calcium intake is to multiply the quantity of dairy servings consumed per day by 300 mg. One serving is 8 oz (240 mL) of milk or yogurt or 1 oz of bad luck. farmer’s cheese and frozen dessert contain approximately 150 mg of calcium per 4 oz (120 mL). Other foods during a well-balanced diet (dark green vegetables, some nuts, breads, and cereals) supply a median of 100 mg of calcium daily Some cereals, soy products, and fruit juices are fortified with up to 1000 mg of calcium. While it’s possible to estimate the quantity of calcium in other sources of dietary calcium like green vegetables and nuts, calcium absorption from these sources is more variable.

additionally, vegetables and nuts have much lower calcium content than dairy products in order that way more would wish to be consumed to fulfill daily requirements. Detailed lists of the calcium content of assorted foods are available from the US Department of Agriculture Calcium supplements or increased intake of dairy products should be recommended if dietary calcium intake is below recommended levels. If supplements are needed, it’s important to notice that the intake suggested above reflects the quantity of elemental calcium in supplements, not the entire calcium content. additionally, the overall intake of calcium (diet plus supplements) shouldn’t routinely exceed 2000 mg/day due to the chance of adverse effects ergocalciferol — within the u. s., commercially fortified milk is that the largest source of dietary ergocalciferol, containing approximately 100 int. units of calciferol per 8 oz Thus, cholecarciferol intake is estimated by multiplying the quantity of cups of milk consumed per day by 100. viosterol is additionally found in cod liver oil, but some fish oils also contain high doses of antiophthalmic factor, and so they’re not the most effective source of ergocalciferol Sunlight exposure also increases vitamin D concentrations. However, the employment of sunscreen products effectively blocks vitamin D synthesis. additionally, the skin of these older than 70 years old doesn’t convert D as efficiently as in younger individuals. Thus, fat-soluble vitamin supplements are generally necessary. The safe upper limit for calciferol is unclear but is above 2000 units daily.

SUPPLEMENTS

— In patients requiring calcium and calciferol supplementation, a daily multivitamin is both convenient and economical. However, most multivitamins contain only 400 int. units of fat-soluble vitamin, which is insufficient, and not all individuals require or tolerate multivitamins .) Postmenopausal women with osteoporosis can even increase viosterol and calcium intake by taking plain ergocalciferol supplements (usually 400 units per tablet) and/or calcium supplements that also contain fat-soluble vitamin, usually 200 units per 500 mg or 600 mg of calcium. it’s important to notice that there’s not an instantaneous linear relationship between supplemental dosing and level of serum 250HD. Individuals with low levels at baseline (<10 ng/mL) generally have a rise in 250HD of 1.0 to 1.5 ng/mL for each 100 IU of vitamin D; however, individuals at levels above 20 ng/mL show an attenuated increase in serum 250HD (ie, usually 0.5 ng/mL for each 100 units). Calcium — the foremost widely available calcium supplements are carbonate and calcium citrate carbonate is cheapest and thus often a decent first choice. However, there are some limitations to its use compared with calcium citrate:

  • Calcium carbonate absorption is healthier when crazy meals; compared, calcium citrate is well absorbed within the fasting state and is best or equally absorbed compared with carbonate dotty a meal. this could be particularly important in patients with achlorhydria. Thus, it seems prudent to require carbonate with meals, since it’s often hard to grasp who has achlorhydria.
  • Calcium carbonate is additionally poorly absorbed in patients taking proton pump inhibitors or H2 blockers. We usually recommend calcium citrate as a primary line calcium supplement in these patients.
  • Many natural carbonate preparations like oyster shells or bone meal contain some lead, and tiny amounts are present in refined (antacid) carbonate or calcium citrate The low lead levels in calcium supplements are unlikely to be a health risk, because calcium blocks lead absorption Dosing  — The intake recommendations given above seek advice from the number of elemental calcium . As an example, carbonate is 40 percent elemental calcium, in order that 1250 mg of carbonate contains 500 mg of elemental calcium. The dose of elemental calcium is listed on most supplement labels. Calcium supplementation in more than 500 mg/day should be in divided doses. Higher individual doses are related to a plateau in calcium absorption that will prevent the attainment of positive calcium balance Side effects   — normally, concern that prime dietary calcium increases the chance of nephrolithiasis in otherwise healthy patients is unfounded, because the incidence of stone formation appears to be reduced in both men and ladies This issue is discussed well separately. However, calcium supplements are related to an increased risk of kidney stones . The Women’s Health Initiative (WHI) trial described above also reported an increased risk of kidney stones in postmenopausal women who were supplemented with calcium and cholecarciferol compared with placebo Other potential side effects of high calcium intake include dyspepsia and constipation. additionally, calcium supplements interfere with the absorption of iron and hormone and, therefore, these medications should be taken at different times. The effect of calcium supplementation on risk of upset is controversial There is also benefits of calcium supplementation on risk factors, like a discount in weight, pressure, and in serum cholesterol concentrations (of about 5 percent) in patients with mild to moderate hypercholesterolemia. .) within the WHI trial described above, 36,282 postmenopausal women ages 50 to 69 years were randomly assigned to calcium (1000 mg/day) plus fat-soluble vitamin (400 int. units/day) or placebo (personal supplementation of up to 1000 mg additional calcium and 600 units viosterol was also allowed) upset was a prespecified secondary outcome . At baseline, mean calcium intake (diet plus supplements) was approximately 1150 mg/day, and 54 percent of participants were taking non-protocol calcium supplements. After seven years, calcium plus viosterol supplementation had no significant effect on the incidence of myocardial infarct (confirmed in 411 and 390 women assigned to calcium/vitamin D and placebo, respectively; HR 1.05, 95% CI 0.91-1.20) or stroke (362 versus 377 strokes, HR 0.95, 95% CI 0.82-1.10). However, the findings of two meta-analyses evaluating calcium or calcium with or without ergocalciferol supplementation (eight and nine trials, respectively) raised some concern about an increased risk of infarct (MI) in patients randomly assigned to calcium versus placebo (166 versus 130 MIs, pooled relative risk 1.27, 95% CI 1.01-1.59) or calcium with or without D versus placebo (374 versus 302 MIs, RR 1.24, 95% CI 1.07-1.45 . The meta-analyses had several limitations. The trials within the meta-analyses weren’t designed to explore cardiovascular outcomes, which weren’t uniformly collected or adjudicated. Patient level data weren’t available from all the trials. In one in all the meta-analyses, only data from a subgroup of participants within the Women’s Health Initiative (those not taking personal calcium supplements at randomization), instead of all participants, were included within the analysis The baseline dietary calcium intake within the trials ranged from 750 to 1240 mg daily and therefore the addition of calcium supplements raised total intake over 1500 to 2000 mg daily in many patients, which is on top of recommended. Another meta-analysis evaluated the consequences of supplementation with calcium, vitamin D, or both on upset (CVD), including CVD death, nonfatal coronary cardiopathy or MI, and nonfatal stroke in a very pooled analysis of 4 trials, calcium supplementation failed to significantly increase the chance of CVD events compared with placebo (RR 1.14, 95% CI 0.92-1.41). In these trials, dietary intake of calcium ranged from 800 to 900 mg daily and also the dose of calcium supplements ranged from 600 to 1200 mg daily. during a pooled analysis of two trials (one of which was the Women’s Health Initiative and included data from all participants), combined vitamin D and calcium supplementation versus double placebos (RR 1.04, 95% CI 0.92-1.18) and ergocalciferol alone compared with placebo (RR 0.90, 95% CI 0.77-1.05) also failed to significantly increase the danger of CVD, and there was a suggestion of a benefit in CVD reduction with vitamin D alone. As within the meta-analyses described above, none of the trials were designed to assess the consequences of calcium or cholecarciferol on cardiovascular outcomes. A prospective cohort study (23,980 participants with mean follow-up of 11 years) published after the meta-analyses showed a big reduction in MI risk in patients with higher versus lower total dietary calcium intake (HR 0.69, 95% CI 0.50-0.94 for the third compared with lowest quartile of total dietary calcium intake) . in an exceedingly separate analysis using the identical cohort, there was a big increased risk of myocardial infarct in users versus nonusers of calcium supplements (HR 1.86, 95% CI 1.17-2.96). However, there have been only 20 events within the calcium group, which reduced the precision of the analysis. Thus, it’s unclear from the current data whether intake of dietary calcium versus calcium supplements confers different cardiovascular risks. Randomized trials of calcium and vitamin D supplementation with CVD events ascertained as a primary endpoint are required to see if calcium supplementation is related to an increased occurrence of those events . within the interim, we advise combined calcium and vitamin D supplementation, as reviewed above Vitamin D  — D is mostly easier to soak up than calcium and it should be taken together dose with or without food. the 2 commonly available varieties of fat-soluble vitamin supplements are ergocalciferol and cholecalciferol. Some but not all studies suggest that cholecalciferol (vitamin D3) increases serum 25OHD more efficiently than does ergocalciferol (vitamin D2 . additionally, ergocalciferol2 isn’t accurately measured all told vitamin D assays For these reasons, we recommend supplementation with cholecalciferol when possible, instead of ergocalciferol. Calcitriol is that the most active metabolite of ergocalciferol. It can frequently cause hypercalcemia and/or hypercalciuria, necessitating close monitoring and adjustment of calcium intake and calcitriol dose. Therefore, we don’t recommend calcitriol for fat-soluble vitamin supplementation in osteoporosis. However, calcitriol or other D analogs are a crucial component of therapy for secondary hyperparathyroidism in chronic nephrosis .)

 Adverse effects

— The intake at which the dose of D becomes toxic isn’t clear. In 2010, the Institute of medication defined the Safe Upper Limit for viosterol as 4000 int. units per day However, higher doses are sometimes required for the initial treatment of viosterol deficiency. .) it’s important to inquire about additional dietary supplements (some of which contain viosterol) that patients could also be taking before prescribing extra vitamin D [ 83 ]. Excessive D, especially combined with calcium supplementation, may cause hypercalcemia, hypercalciuria, and kidney stones. additionally, chronically high levels of 250HD (exceeding 40 and 50 ng/mL [100 and 125 nmol/L], respectively) are found in some association studies to be linked to a modest increase in risk of some cancers (eg, pancreatic) and mortality. and “Vitamin D and extraskeletal health”, section on ‘Mortality’ .) More studies are needed to define the upper level of serum 250HD that’s safe. Coexisting medical problems   — Many individuals with osteoporosis have underlying medical conditions that predispose to osteoporosis. Recommendations for calcium and viosterol supplementation may vary with the underlying condition

. fat-soluble vitamin deficiency

— viosterol deficiency may result from inadequate intake combined with lack of sun exposure, malabsorption, or genetic abnormalities in vitamin D metabolism. viosterol deficiency or insufficiency is commonly overlooked, unless 25OHD concentrations are measured. Commonly used antiresorptive agents, like bisphosphonates, could also be less effective in patients with occult cholecarciferol deficiency. additionally, hypocalcemia can occur in patients with D deficiency who are treated with bisphosphonates, particularly when administered intravenously, before repletion of fat-soluble vitamin Individuals with ergocalciferol deficiency generally require higher doses of viosterol initially, followed by maintenance doses as described above. The treatment of calciferol deficiency is reviewed separately Primary hyperparathyroidism   — Adequate dietary calcium (800 to 1000 mg daily) and viosterol supplementation (400 to 600 units daily) is inspired for patients with primary hyperparathyroidism. Cautious calcium supplementation is safe in individuals with poor dietary intake. Patients with overt calciferol deficiency may have more clinically significant hyperparathyroidism and will require cautious supplementation with higher doses of vitamin D Underlying gastrointestinal disease   — Patients with malabsorption or short-bowel syndrome may have beyond normal calcium and calciferol requirements thanks to diminished calcium absorption. This problem can occur even with relatively minor disruption of gastrointestinal function, as in patients who have undergone gastrectomy Several factors can contribute to the malabsorption of calcium in these patients:

  • Reduced gastric acidity and mild generalized malabsorption thanks to impaired mixing of food with pancreatic secretions and decreased gut transit time.
  • Binding of calcium to fatty acids in patients with steatorrhea
  • Vitamin D deficiency because of both malabsorption and also the tendency to avoid milk Optimal calcium and D supplementation must be determined empirically and must be adjusted so as to normalize the serum concentrations of calcium, phosphate, alkaline phosphatase, 25OHD, and endocrine, and 24-hour urinary calcium excretion The American Gastroenterological Association (AGA) technical review and guideline for osteoporosis in gastrointestinal diseases yet as other AGA guidelines, will be accessed through Proton pump inhibitor therapy  — carbonate is poorly absorbed in patients taking proton pump inhibitors or H2 blockers. We usually recommend calcium citrate as a primary line calcium supplement in these patients. Diuretic therapy  — Concomitant administration of diuretics can influence calcium balance. Loop diuretics increase calcium excretion, while thiazide diuretics have a hypocalciuric effect that may protect against calcium stones and possible bone loss. The effect of diuretics on optimal dietary calcium intake isn’t known. monogenic disorder   — Patients with advanced monogenic disorder are usually deficient in ergocalciferol, and that they require quite the standard recommended dose for young adults (eg, over 400 int. units/day).

Granulomatous diseases

— Individuals with granulomatous diseases, like sarcoidosis, are often treated with glucocorticoids and thus have an increased risk of osteoporosis. However, they also tend to own hypercalcemia and hypercalciuria because of extrarenal production of calcitriol by activated macrophages and consequent increased intestinal absorption of calcium In patients with sarcoidosis and osteoporosis, serum and urinary calcium and ergocalciferol concentrations must be carefully monitored if supplements are required

 INFORMATION FOR PATIENTS

 

— UpToDate offers two varieties of patient education materials, “The Basics” and “Beyond the fundamentals.” the fundamentals patient education pieces are written in plain language, at the 5 th to six th grade reading level, and that they answer the four or five key questions a patient might need a couple of given condition. These articles are best for patients who need a general overview and preferring short, easy-to-read materials. Beyond the fundamentals patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the ten th to 12 th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to the current topic. We encourage you to print or e-mail these topics to your patients. (You also can locate patient education articles on a spread of subjects by searching on “patient info” and also the keyword(s) of interest.) SUMMARY and proposals   — Adequate calcium and cholecarciferol intake may end up in positive calcium balance and a discount within the rate of loss of bone; the effect upon fracture risk is a smaller amount clear, although combined calcium and calciferol supplementation appears to cut back fracture risk. Calcium and viosterol supplementation are relatively inexpensive and appear reasonable to recommend in patients with a coffee dietary intake.

  • We suggest calcium and D supplementation in patients with osteoporosis and inadequate dietary intake In postmenopausal women, 1200 mg of elemental calcium daily, total diet plus supplement, and 800 int. units of calciferol daily are suggested. Although the optimal intake (diet plus supplement) has not been clearly established in premenopausal women or in men with osteoporosis, 1000 mg of calcium (total diet plus supplement) and 400 to 600 int. units of calciferol daily are generally suggested. The dose of calcium and cholecarciferol may vary in individuals with coexisting medical conditions.
  • Individuals with cholecarciferol deficiency require higher doses of ergocalciferol. The evaluation and treatment of fat-soluble vitamin deficiency are reviewed separately
  • In most people, carbonate loving meals is adequate for supplementation and is inexpensive. However, we recommend calcium citrate in patients taking proton pump inhibitors or H2 blockers or who have achlorhydria
  • We suggest cholecalciferol (vitamin D3), when available, instead of ergocalciferol (vitamin D2) for calciferol supplementation
  • The total intake of calcium (diet plus supplements) mustn’t routinely exceed 2000 mg/day. The safe upper limit for D is 4000 int. units daily

Drug therapy of obesity

Along with diet, exercise, and psychotherapy, drug therapy could also be a helpful component of treatment for overweight or obese patients. The role of drug therapy has been questioned, however, thanks to concerns about efficacy, safety, and therefore the observation that weight slows then plateaus with continued treatment, and most patients regain weight when their weight-loss drugs are stopped.
The decision to initiate drug therapy in overweight subjects should be made only after a careful evaluation of risks and benefits the primary step is evaluation of the patient, which should include determination of the body mass index (BMI), the distribution of fat based upon the waist circumference, and investigations for comorbid conditions like diabetes, dyslipidemia, hypertension, and heart condition
Anti-obesity drugs is useful adjuncts to diet and exercise for obese adults with a BMI greater than 30 kg/m2, who have did not achieve weight loss goals through diet and exercise alone. an attempt of drug therapy is additionally warranted in patients with a BMI of 27 to 29.9 kg/m2 with comorbidities, or in those in whom gastrointestinal bypass surgery is being considered.
This topic will review drug therapy for weight loss in obese subjects Other treatments are discussed separately.


GOALS OF THERAPY

— The goal of any treatment, including drug therapy, for overweight subjects must be realistic.
• The ideal outcome could be a return to normal weight, but this is often usually unrealistic. In one study, as an example, subjects were asked about their dream weight, and this was later compared with the particular weight loss achieved; no subject achieved their dream weight and few were pleased with the burden loss they achieved Thus, the clinician and also the patient have to come to a mutual affection of the realities of weight loss.
• Success could also be measured by the degree of weight loss and improvement in associated risk factors. Weight loss should exceed 2 kg during the primary month of drug therapy (one pound per week), fall over 5 percent below baseline between three to 6 months, and remain at this level to be considered effective. A weight loss of 5 to 10 percent can significantly reduce the danger factors for diabetes and disorder in higher risk patients Improvement in baseline risk factors after weight loss is a vital criterion within the determination of whether to continue therapy
• In drug trials, weight loss of 10 to fifteen percent using both drug and behavioral intervention is taken into account a awfully good response, and weight loss exceeding 15 percent is taken into account a wonderful response. This degree of weight loss generally has substantial benefits, including lowering force per unit area and improving serum lipid concentrations, increasing insulin sensitivity, and reducing hyperglycemia, and should reduce risk of mortality. However, a drug may produce side effects which will reduce its overall benefits
• The maximal duration of published treatment results is four years for orlistat . If patient response is sweet, using the factors noted above, and also the patient wishes to continue orlistat, this might be considered after acknowledging the dearth of long run data and obtaining the patient’s willingness to continue.
• Drug therapy doesn’t cure obesity. Obese subjects given drugs should be advised that when the maximal therapeutic effect is achieved, weight loss ceases. When drug therapy is discontinued, weight is anticipated to rise.
• When overweight patients have diabetes, depression, behavioral problems, or upset, it’s important to pick drugs for these diseases which produce weight loss, instead of weight gain, when benefits in total outweigh risks of adverse effects. Several drugs are well-known to supply weight gain and may be avoided if good alternatives are available. Although weight loss is often desirable, it must be balanced against other factors (ability to attain desired glycemic control, other side effects and risks of meds, and expense).
• Achieving and maintaining weight loss is created difficult by the reduction in energy expenditure that’s related to weight loss. In one report, as an example, maintenance of weight at 10 percent below the baseline weight in obese subjects was related to an 8 kcal/kg reduction in total energy expenditure


• OUR APPROACH

— In meta-analyses of randomized trials comparing pharmacologic therapy with placebo, all active drug interventions are effective at reducing weight compared with placebo Many of the trials within the meta-analyses have serious limitations, including short duration of study, high attrition rates, heterogeneity, and inadequate reporting of important clinical outcomes (eg, cardiovascular outcomes). additionally, there are few head-to-head trials comparing the individual therapies. Thus, the choice to use pharmacologic therapy should be individualized, weighing the potential benefits with the risks of the agents. the selection of antiobesity drugs is therefore often governed by the comorbidities and relative contraindications present within the individual patient. Our approach outlined below relies upon the available clinical test evidence and clinical expertise.

  • Counsel all overweight (BMI 25 to 29.9 kg/m2) and obese patients (BMI ≥30 kg/m2) on diet, lifestyle, and goals for weight loss.
    • Pharmacologic therapy could also be offered to those with a BMI >30 kg/m2 or a BMI of 27 to 29.9 kg/m2 with comorbidities, who have didn’t achieve weight loss goals through diet and exercise alone.
    • Pharmacologic options to be used in patients include orlistat , lorcaserin , combination phentermine-topiramate , phentermine , benzphetamine , phendimetrazine , and diethylpropion of those options, we prefer orlistat as initial therapy due to its efficacy and long-term safety record. particularly, we favor orlistat over other pharmacologic options for patients with obesity and dyslipidemia and/or diabetes. However, unpleasant gastrointestinal side effects may limit the utilization of orlistat for the treatment of obesity. Lorcaserin is another option with similar efficacy as orlistat. It appears to own fewer adverse effects than orlistat, although long-term safety data are limited. Like orlistat, it should be utilized in obese patients with diabetes, hypertension, and/or dyslipidemia. Lorcaserin should be discontinued if patients don’t lose 5 percent of their weight in 12 weeks.Combination phentermine- topiramate is an option for obese men or women without hypertension or coronary cardiovascular disease. The efficacy of phentermine-topiramate appears to be greater than orlistat or lorcaserin, but it should have more side effects (eg, increased vital sign, dose-related increase within the incidence of psychiatric [eg, depression, anxiety] and cognitive [eg, disturbance in attention] adverse events). it should be a suitable option for a patient with an obesity-related comorbidity like sleep disorder, who doesn’t have any upset. If a patient doesn’t lose 5 percent of weight after 12 weeks on the best dose, phentermine-topiramate should be discontinued gradually. this mix may increase risk of fetal malformations and it should thus be used with cause in women of kid bearing age who should have a bioassay before its use and monthly thereafter.

    Phentermine, benzphetamine, phendimetrazine, and diethylpropion are only approved for short-term use, have more side effects, and also the potential for abuse Thus, we recommend not using these drugs for long-term weight loss. If they’re prescribed for short-term weight loss, clinicians would serve their patients well by providing them written description of the bounds of those drugs so they’ll consent to their use.
    • For patients with specific comorbidities, we recommend a weight-centric approach to chronic disease management, trying, if possible, to pick the drugs to treat the comorbidity which will produce weight loss, instead of weight gain As an example, for patients with or at high risk for developing diabetes, metformin doesn’t cause weight gain and will cause weight loss in some Exenatide , liraglutide , and pramlintide are related to weight loss in patients with type 2 diabetes, whereas sulfonylureas, thiazolidinediones, glinides, and insulin are related to weight gain. However, for patients with diabetes, weight loss must be balanced against other factors (ability to attain desired glycemic control, other side effects and risks of medicines, and expense). A drug that ends up in better glycemia at the expense of some more kg of weight gain should be preferable to dearer, side-effect laden drugs that don’t achieve goal glycemia For patients with obesity and depression, we decide antidepressants that are weight neutral or produce weight loss, instead of weight gain
    • Bariatric surgery should be considered for patients with BMI ≥40 kg/m2 who have failed diet, exercise, and drug therapy Individuals with BMI >35 kg/m2 and comorbidities (hypertension, impaired glucose tolerance, DM, dyslipidemia, sleep apnea), who have failed diet, exercise, and drug therapy, are potential surgical candidates, assuming that the anticipated benefits outweigh the prices, risks, and side effects of the procedure. Bariatric surgery should be performed at high-volume centers with experienced surgeons Our approach is basically per published guidelines
    The efficacy, dosing, and adverse effects of every drug are described below.

DRUGS THAT ALTER FAT DIGESTION

Orlistat — Orlistat is offered for the long-term treatment of obesity. It alters fat digestion by inhibiting pancreatic lipases Thus, fat isn’t completely hydrolyzed and fecal fat excretion is increased. In normal subjects eating a diet that contains 30 percent fat, orlistat causes a dose-dependent increase in fecal fat excretion that peaks when approximately 30 percent of ingested fat isn’t digested.
Orlistat is obtainable in 120 mg capsules. The recommended dose is 120 mg thrice daily. A lower dose (60 mg) over-the-counter version is approved and available in some countries, including the u. s.. Two of the 60 mg over-the-counter capsules are the identical jointly of the 120 mg capsules. We typically advise patients to require a multivitamin at bedtime because orlistat may decrease the absorption of fat soluble vitamins
Pharmacology — but 1 percent of an oral dose of orlistat is absorbed. What little is absorbed is degraded into two major metabolites. Orlistat doesn’t alter the pharmacokinetics of digoxin , phenytoin , warfarin , glyburide , oral contraceptives, alcohol, furosemide , captopril , nifedipine , or atenolol . However, absorption of fat-soluble vitamins could also be decreased by orlistat. For patients taking warfarin, a decrease in vitamin K may necessitate a discount within the dose of warfarin
Efficacy — The efficacy of orlistat in facilitating weight loss has been demonstrated in several randomized trials and in meta-analyses during a meta-analysis of 12 trials that included patients with and without diabetes and reported data with 12-month outcomes, patients randomly assigned to orlistat plus a behavioral intervention lost 5 to 10 kg (8 percent of baseline weight) compared with 3 to six kg within the control group (placebo plus behavioral intervention), for a mean placebo-subtracted difference of three kg (95% CI -3.9 to -2.0 kg) Weight loss was maintained with up to 24 to 36 months of orlistat treatment In another meta-analysis, orlistat was equally effective in Caucasians and ethnic group groups
In one amongst the longest trials, a four-year double-blind trial, 3304 overweight patients, 21 percent of whom had impaired glucose tolerance, were randomly assigned to placebo or orlistat During the primary year, weight loss was greater within the orlistat-treated group (11 percent compared with 6 percent below baseline within the placebo-treated group) Over the remaining three years of the trial, there was alittle regain in weight, specified by the top of 4 years, the orlistat-treated patients were 6.9 percent below baseline compared with 4.1 percent for those receiving placebo. There was a 37 percent reduction within the conversion of patients from impaired glucose tolerance to diabetes, essentially all of which occurred within the patients with impaired glucose tolerance at enrollment into the trial. In other trials in patients with diabetes, orlistat resulted in significantly more weight loss and reduce in hemoglobin A1C at one year than placebo
In a subsequent trial published after the meta-analyses (146 obese patients [mean BMI 39.3]), the mix of orlistat and an occasional fat diet (<30 percent of daily energy) resulted in similar weight loss (approximately 9 percent) as a low-carbohydrate ketogenic diet (initially <20 g carbohydrate/day
In summary, many clinical trials have demonstrated that initial weight loss is larger which weight regain is slowed by orlistat , as compared with lifestyle/placebo.
Other beneficial effects — Orlistat improves some serum lipid values over is explained by weight reduction alone in a very multicenter trial, as an example, serum total and cholesterol concentrations decreased by 4 to 11 and 5 to 10 percent, respectively, in subjects treated with a weight-maintaining diet plus 30 to 360 mg of orlistat per day for eight weeks These decreases were probably associated with fecal fat loss. Others have reported a discount in postprandial lipemia related to orlistat therapy


Side effects

— The predominant side effects of orlistat therapy are gastrointestinal, including intestinal borborygmi and cramps, flatus, fecal incontinence, oily spotting, and flatus with discharge in a very meta-analysis of nine clinical trials, these side effects occurred at frequency rates of 15 to 30 percent, and cared-for occur early and to subside as patients learned the way to avoid these problems by avoiding high fat diets and sticking to the recommended intake of no over 30 percent fat. There was no evidence of an increased risk of gallstones, renal stones, or cardiovascular or central system events.
Absorption of vitamins A and E and beta-carotene is also slightly reduced in some studies of patients receiving orlistat . within the meta-analysis noted above, levels of fat-soluble vitamins (A, D, E, K) and beta-carotene were lowered by orlistat therapy, with ergocalciferol the foremost frequently affected. it’s advisable to allow vitamin supplements to patients treated with this drug. Orlistat doesn’t seem to affect the absorption of other drugs, with the exception of cyclosporine .
Severe liver injury has been reported rarely with the utilization of orlistat ]. A US Food and Drug Administration review identified 13 reports of severe liver injury, 12 of which occurred outside of the us. Over the 10-year period of the review, an estimated 40 million people worldwide used orlistat. A causal relationship has not been established. Nevertheless, patients who take orlistat should contact their health care provider if itching, jaundice, pale color stools, or anorexia develop.
Oxalate-induced acute kidney injury has also been reported in orlistat users]. Malabsorption syndromes are a risk factor for calcium oxalate stones..) Similarly, fat malabsorption induced by orlistat may end in the binding of enteric calcium. When less calcium is obtainable within the intestinal lumen to bind oxalate, intestinal oxalate absorption and urinary oxalate excretion increase. Free oxalate are often deposited within the renal parenchyma, leading to acute kidney injury. Orlistat mustn’t be employed in patients with a history of calcium oxalate stones.

SEROTONIN AGONISTS

Lorcaserin — Serotonin reduces food intake in animals and masses, and thus agonists to appropriate serotonin receptors are potentially valuable drugs. Lorcaserin may be a selective agonist of the serotonin 2C receptor. It activates central serotonin 2C receptors with a functional selectivity of roughly 15 and 100 times over that for serotonin receptors 2A and 2B, respectively. It reduces appetite and thereby reduces weight in men and girls Nonselective serotonergic agonists, like fenfluramine and dexfenfluramine, also enhanced weight loss in clinical trials. However, they increased the danger of serotonin-associated cardiac valvular disease, thought to occur through activation of serotonin receptor 2B. thanks to its selective agonism of serotonin receptor 2C, lorcaserin theoretically shouldn’t have similar cardiac effects. However, there are few long-term data.
In 2012, the us Food and Drug Administration (FDA) approved lorcaserin as an addition to a reduced-calorie diet and exercise for patients who are obese (BMI ≥30 kg/m2) or overweight (≥27 kg/m2) with a minimum of one medical comorbidity, like type 2 diabetes, hypertension, high cholesterol, or sleep disorder. Lorcaserin appears to possess similar efficacy as and fewer adverse effects than orlistat , although long-term safety data are limited


Efficacy

— The efficacy of lorcaserin appears almost like that of orlistat (mean difference in weight loss between active and placebo treated groups approximately 3 to 4 kg) and maybe slightly but that of phentermine-topiramate and sibutramine (no longer available in most countries).
In one in all the longer randomized trials, 3182 obese adults (BMI 36) were randomly assigned to lorcaserin (10 mg) or placebo twice daily for one year, followed by a 1 year extension period All subjects participated during a lifestyle modification program that included nutritional and exercise counseling. After one year, the proportion of patients with a discount in baseline weight of 5 percent or more was greater in patients within the lorcaserin group (47.5 versus 20.3 percent). Approximately 50 percent of participants remained within the trial during year two. The patients within the placebo group continued to receive placebo, whereas the patients within the lorcaserin group were randomly reassigned to receive lorcaserin or placebo. Among patients who received lorcaserin during year one and successfully lost 5 percent or more of their baseline weight, a greater proportion of patients who received lorcaserin than placebo during year two maintained the burden loss (67.9 versus 50.3 percent). Those participants who were reassigned to placebo gained back weight during year two. At the tip of the trial, their mean weight was almost like people who had received placebo for 2 years.
In addition to weight loss, lorcaserin had beneficial effects on surrogate markers of cardiovascular and diabetes risk, including slight but significant decreases in systolic and diastolic blood pressures, heart rate, total and LDL cholesterol, C-reactive protein, fibrinogen, fasting glucose and insulin levels.
Similar findings were reported in other trials, as illustrated by the following:
• In a one-year randomized trial in 4008 patients, a significantly greater proportion of patients assigned to lorcaserin (10 mg twice daily or once daily) compared with placebo lost a minimum of 5 percent of baseline weight (47.2, 40, and 25 percent, respectively) The mean change in weight from baseline was -5.8, -4.7, and -2.9 kg, respectively.
• In another one-year trial, 604 patients with type 2 diabetes were randomly assigned to lorcaserin (10 mg once daily or twice daily) or placebo the bulk of patients were treated with metformin , a sulfonylurea, or both. Patients treated with exenatide , pramlintide , or insulin were excluded from participation within the study. After one year, more patients lost ≥5 percent of their weight with lorcaserin compared with placebo (44.7, 37.5, and 16.1 percent, respectively). There was also a big reduction in glycated hemoglobin (-1.0, -0.9, and -0.4 percentage points, respectively) and fasting blood sugar (-28.4, -27.4, and -11.9 mg/dL [1.58, 1.52, and 0.66 mmol/L], respectively) within the lorcaserin compared with placebo group.
All of the trials described above were limited by a high dropout rate, which ranged from 35 to 50 percent. These levels of “dropouts” would invalidate most other clinical trials. additionally, slightly over 50 percent of patients taking lorcaserin for one year failed to lose 5 percent of their baseline weight.
Adverse effects — Adverse effects of lorcaserin were generally mild and included headache, upper respiratory infections, nasopharyngitis, dizziness, and nausea, occurring in 18, 14.8, 13.4, 8, and 7.5 percent of patients, respectively Headaches, nausea, back pain, and nasopharyngitis, particularly, occurred with greater frequency than with placebo In patients with type 2 diabetes on oral agents, lorcaserin-induced weight loss may increase the danger of symptomatic hypoglycemia, necessitating a discount in dose of diabetes medications In two of the trials, there was no significant increase within the incidence of serotonin-associated valvulopathy (as assessed by echocardiography at week 52) within the smaller trial of lorcaserin in patients with type 2 diabetes, the incidence of valvulopathy at week 52 was 2.9 and 0.5 percent within the lorcaserin and placebo groups, respectively the overall number of events was small, reducing the precision of the analysis. Neuropsychiatric side effects weren’t significantly increased in any of the trials.


Dosing and contraindications

— The recommended dose of lorcaserin is 10 mg twice daily, in love or without food, and there’s no need for a titration period. The response to therapy should be evaluated by week 12. Lorcaserin should be discontinued if patients don’t lose 5 percent of weight in 12 weeks No dose adjustment is required in patients with mild renal (creatinine clearance 50 to 80 mL/min) or mild to moderate hepatic (Child-Pugh score 5 to six and seven to 9, respectively) impairment.
Lorcaserin mustn’t be utilized in individuals with creatinine clearance <30 mL/min. it’s contraindicated during pregnancy. additionally, lorcaserin mustn’t be used with other serotonergic drugs

eg, selective serotonin reuptake inhibitors, selective serotonin-norepinephrine reuptake inhibitors, bupropion , tricyclic antidepressants, and monamine oxidase inhibitors) due to the theoretical potential for serotonin syndrome. Lorcaserin inhibits CYP 2D6-dependent metabolism, and might therefore increase exposure of medicine that are CYP 2D6 substrates (eg, dextromethorphan ).


SYMPATHOMIMETIC DRUGS

— The noradrenergic sympathomimetic drugs:
• Stimulate the discharge of norepinephrine or inhibit its reuptake into nerve terminals ( phentermine , diethylpropion , benzphetamine , phendimetrazine
• Block norepinephrine and serotonin reuptake (sibutramine – now withdrawn from the market)
• Directly work adrenergic receptors (phenylpropanolamine – now withdrawn from the market)
• May increase pressure
Sympathomimetic drugs reduce food intake by causing early satiety. The currently available sympathomimetic drugs ( phentermine , diethylpropion , benzphetamine , and phendimetrazine ) are only approved for the short-term (up to 12 weeks) treatment of obesity. Although phentermine is that the most generally prescribed weight loss drug, we advise not using sympathomimetic drugs thanks to their potential side effects, potential for abuse, and limited duration of use. they’re contraindicated in patients with coronary cardiovascular disease, hypertension, hyperthyroidism, or in patients with a history of misuse.
Phentermine together with topiramate is reviewed separately below.

Pharmacology

— All of the sympathomimetic drugs are rapidly absorbed after oral administration, and peak plasma concentrations are reached within one to 2 hours Their plasma half-lives are short, aside from the active metabolites of sibutramine (which is that the only drug during this group that has active metabolites). All the drugs during this class are metabolized to inactive products within the liver. the most important route of elimination is via the kidneys.
Phentermine and diethylpropion are Schedule IV drugs, a regulatory classification suggesting potential for abuse, although the particular potential is low. Benzphetamine and phendimetrazine are Schedule III drugs. These drugs are approved just for short-term administration, which is widely interpreted as up to 12 weeks. they need been utilized in combination with other drugs


Efficacy

— in an exceedingly systematic review of trials evaluating the efficacy of sympathomimetic drugs, the common weight loss for patients taking a full of life drug for four weeks was 0.23 kg (0.5 pounds) per week quite for placebo In trials of up to 25 weeks duration, net weight loss with diethylpropion compared with placebo ranged from 1 to 10 kg. in a very 36 week trial, both continuous and intermittent administration of phentermine led to more weight loss than placebo (net weight loss 7.4 kg). Weight loss slowed during the drug-free periods within the intermittently-treated patients, but accelerated when treatment was resumed
Safety — All sympathomimetic drugs can increase pulse rate, pressure level, and cause insomnia, dry mouth, constipation, and nervousness. within the clinical trials of sibutramine, systolic and diastolic pressure level increased on the average by 1 to three mmHg (including patients with hypertension controlled with a medicament with or without concomitant thiazide treatment) and pulse increased by approximately four to 5 beats per minute. in an exceedingly trial of sibutramine or placebo in over 10,000 patients with or at high risk for upset, 92 percent of whom failed to meet current labeling criteria, sibutramine was related to a better risk of nonfatal myocardial infarct (4.1 versus 3.2 percent, HR 1.28, 95% CI 1.04-1.57) and nonfatal stroke (2.6 versus 1.9 percent, HR 1.36, 95% 1.04-1.77) Based upon this information, the ecu Medicines Agency suspended the marketing of sibutramine across the eu Union In 2010, the US Food and Drug Administration and Health Canada also removed sibutramine from the market
Phenylpropanolamine was also far from the market thanks to atiny low but significant risk of hemorrhage in women
Ephedrine could be a sympathomimetic amine with a chronic duration of action, increased peripheral actions, and decreased central actions on adrenergic receptors. Ephedra and ephedra alkaloids (Ma Huang) are a gaggle of ephedrine-like molecules found in plants. Ephedrine stimulates weight loss a minimum of partly by increasing thermogenesis and by reducing food intake. thanks to safety concerns, ephedrine with or without caffeine and also the ephedra alkaloids don’t seem to be approved for treatment of obesity and are aloof from the market


ANTIDEPRESSANTS

— Drugs wont to treat depression can increase weight, be weight neutral, or reduce weight. When efficacy is equivalent, it’s important for the clinician to pick antidepressant drugs that are weight neutral or cause weight loss
and beta-carotene were lowered by

Bupropion — Bupropion may be a drug approved for the treatment of depression and for the utilization in prevention of weight gain when trying to prevent smoking it’s a relative of diethylpropion , an approved drug for treating obesity. It probably acts through modulating the action of norepinephrine during a six-month trial of bupropion SR (300 or 400 mg/day) versus placebo with a six-month blinded extension where all patients received active medication, both doses of bupropion produced significantly more weight loss than placebo During the six-month extension the load loss was largely maintained.

ANTIEPILEPTIC DRUGS

— Some antiepileptic drugs cause weight gain, others are weight neutral, and some produce weight loss. When efficacy is equivalent, it’s important for the clinician to pick antiepileptic drugs that are weight neutral or cause weight loss).
Topiramate — Topiramate is approved to be used as an antiepileptic and for the treatment of migraine. In clinical studies, its use was related to weight loss, prompting evaluation of its efficacy and safety as an anti-obesity agent [
In a six-month dose-ranging trial, topiramate produced a net weight loss versus placebo of three.7 kg (2.17 to 5.23 kg). in a very meta-analysis of six trials, the typical six-month weight loss was 6.51 percent (4.77 to 8.25 percent) with a result of about 2 percent Significant side effects of topiramate included paresthesias, somnolence, and difficulty concentrating. Topiramate has also been related to acidosis. We don’t recommend its use as one agent for the management of obesity at now
Topiramate employed in combination with phentermine is reviewed below.
Zonisamide — Zonisamide is an anticonvulsant that has serotonergic and dopaminergic activity additionally to inhibiting sodium and calcium channels. Weight loss was noted in clinical trials for the treatment of epilepsy, prompting an attempt for obesity. A one-year trial investigated its use in 225 obese individuals (mean BMI 37.6 kg/m2) who followed a calorie-restricted diet and were randomly assigned to zonisamide (200 or 400 mg/day) or placebo The high dose zonisamide group lost significantly more weight than the placebo group (mean weight loss 7.3 versus 4.0 kg). Weight loss within the low dose zonisamide group (4.4 kg) was like placebo. Side effects (gastrointestinal, central system, and psychiatric adverse events) occurred more commonly with zonisamide than with placebo. We don’t recommend its use for the management of obesity at now..)
DIABETES DRUGS


Metformin

— Metformin could be a biguanide that’s approved for the treatment of DM, a disease that’s exacerbated by obesity and weight gain. In one trial of patients with obesity and also the metabolic syndrome, patients receiving metformin lost significantly more weight (1 to 2 kg) than the placebo group
After a mean follow-up of two.8 years within the Diabetes Prevention Program for patients with impaired glucose tolerance, average weight loss was 0.1, 2.1, and 5.6 kg within the placebo, metformin , and lifestyle-intervention groups, respectively in an exceedingly follow-up study, the modest weight loss with metformin was maintained during the 10-year observation period the load loss was directly associated with the extent of adherence. Individuals with high adherence lost about 4.5 kg, whereas people who stopped taking it were comparable in weight to the placebo group Although metformin doesn’t produce enough weight loss (5 percent) to qualify as a “weight-loss drug,” it’d appear to be a really useful choice for overweight individuals at high risk for diabetes. As against most weight loss studies with duration <1 year, the Diabetes Prevention Program had essentially no loss to follow-up in almost three years, making its results far more credible and fewer prone to bias. Metformin is discussed very well elsewhere.)

Pramlintide

— Amylin (also referred to as islet amyloid polypeptide) may be a peptide hormone secreted by pancreatic beta cells in conjunction with insulin in response to nutrient stimuli Pramlintide could be a synthetic analog of human amylin that slows gastric emptying, reduces postprandial rises in glucose concentrations, and improves hemoglobin A1C (A1C) concentrations in patients with type 1 and kind 2 diabetes. It must be by shot. Pramlintide for the treatment of diabetes is discussed well elsewhere
Unlike insulin and lots of other diabetes medications, pramlintide is related to modest weight loss. in a very meta-analysis of eight randomized trials, pramlintide reduced weight compared with placebo (mean difference -2.57 and -2.27 kg, in patients with and without diabetes, respectively). In one amongst the larger trials, 651 patients with type 1 diabetes were randomly assigned to placebo or subcutaneous pramlintide, additionally to their usual insulin therapy. Weight decreased 0.4 kg within the pramlintide group and increased by 0.8 kg within the placebo group]. In other trials of pramlintide in obese patients with or without diabetes, small but significant reductions in weight are reported]

 

Exenatide

— The incretin peptides (glucagon-like polypeptide-1 [GLP-1] and glucose-insulin polypeptide, also called gastric inhibitory polypeptide [GIP]) are gastrointestinal peptides that stimulate glucose-dependent insulin secretion. GLP-1 also inhibits glucagon release and gastric emptying. Exenatide , a long-acting synthetic peptide that’s a GLP-1 receptor agonist, is offered for adjunctive therapy for patients with type 2 diabetes who are inadequately controlled on oral agents. The drug is run subcutaneously twice daily. Dose-dependent weight loss has been reported in trials of exenatide in patients with type 2 diabetes not well controlled on oral agents. These exenatide trials are discussed well elsewhere.

Liraglutide

— Liraglutide is another long-acting GLP-1 analog. it’s available to be used within the u. s. and Europe for the treatment of type 2 diabetes. The drug is run subcutaneously once daily. In diabetes trials, liraglutide was related to a big reduction in weight (2.0 to 2.5 kg) compared with placebo or glimepiride .)
Weight loss has also been reported in patients without diabetes who received liraglutide . As an example, in an exceedingly 20-week randomized trial comparing liraglutide (administered subcutaneously in one in all four daily doses, 1.2 to 3 mg), placebo, and open-label orlistat (120 mg orally 3 times daily) in 564 patients (mean BMI 35), weight loss increased with increasing doses of liraglutide, with mean weight loss starting from 4.8 to 7.2 kg. Patients randomly assigned to any dose of liraglutide lost significantly more weight than those assigned to placebo (mean weight loss 2.8 kg). Patients taking the 2 highest doses of liraglutide (2.4 and 3.0 mg) lost significantly more weight than those assigned to orlistat (6.3, 7.2, and 4.1 kg, respectively).
The two highest doses of liraglutide are above those previously assessed for the treatment of diabetes, and a greater proportion of patients taking these doses reported nausea (37 to 47 percent) and vomiting (12 to 14 percent). Thus, weight loss is also due, in part, to gastrointestinal side effects.
HORMONES — Although injections of human chorionic gonadotropin (hCG) are advertised to help in weight loss, clinical trials fail to support this claim. Oral or sublingual diet drops of hCG are available and are touted to possess the identical benefits as injectable hCG. Among the values claimed for this treatment are loss of 1 to 2 pounds daily, absence of hunger, and maintenance of muscular tonus. Several randomized trials have shown that the hCG diet isn’t more practical than placebo within the treatment of obesity An integral component of the hCG diet is adherence to a awfully low calorie diet (500 kcal/day). Adherence to a really low calorie diet (200 to 800 kcal/day) leads to short-term weight loss. The addition of hCG has not been shown to produce any additional effect. Thus, hCG shouldn’t be used for the treatment of obesity. additionally, very low calorie diets haven’t been shown to be superior to standard diets for long-term weight loss.


COMBINATION DRUGS

— Because the regulation of food intake is controlled by several pathways, it’s been hypothesized that combining two drugs with different mechanisms of action could improve efficacy (and tolerability if utilized in lower doses) compared with single drug therapy.
Phentermine-topiramate — In 2012, the US FDA approved a preparation of phentermine and extended-release topiramate (in one capsule) for adults with a body mass index ≥30 kg/m2 or with a BMI ≥27 kg/m2 with a minimum of one weight-related comorbidity (eg, hypertension, diabetes, dyslipidemia) this mix has been shown to reinforce weight loss within the first year of use, as illustrated by the subsequent trials:
• A combination of controlled-release phentermine-topiramate (7.5/46 mg or 15/92 mg) was compared with placebo in 2487 adults with BMI of 27 to 45 kg/m2 and two or more comorbidities After one year, mean weight loss was greater in those assigned to active treatment (8 to 10 versus 1.4 kg with placebo [8 to 10 percent versus 1.2 percent of baseline bodyweight]). Only 61 percent of participants completed one year of treatment, again calling the results into question.

In a 52 week extension of the above trial (78 percent of eligible subjects participating), mean total weight loss (from baseline to 108 weeks) was significantly better than placebo (9.6, 10.9, and 2.1 kg [9.3, 10.5, and 1.8 percent of baseline bodyweight] for low dose, high dose, and placebo, respectively) Of note, phentermine – topiramate was less effective in increasing weight loss within the second year of use, although most people were able to maintain the load they lost in year one. In those subjects who were able to participate within the second year of the trial, the therapy was well tolerated.
• In another trial, men and ladies with BMI ≥35 kg/m2 were randomly assigned to controlled release phentermine-topiramate (3.75/23 mg or 15/92 mg) or placebo After 56 weeks, mean weight loss was greater within the active treatment groups (mean reduction 6, 12.6, and 1.9 kg [5.1, 10.9, and 1.6 percent of baseline bodyweight]). Among those assigned to active treatment, 45 to 67 percent lost a minimum of 5 percent of baseline weight compared with 17 percent of placebo patients.

The most common adverse events in these trials were xerostomia (13 to 21 versus 2 percent), constipation (15 to 17 versus 6 percent), and paraesthesia (14 to 21 versus 2 percent ]. There was a dose-related increase within the incidence of psychiatric (eg, depression, anxiety) and cognitive (eg, disturbance in attention) adverse events within the active treatment group. Although pressure improved slightly with active therapy, there was a rise in pulse rate (0.6 to 1.6 beats/min) compared with placebo.
This combination drug is contraindicated during pregnancy due to an increased risk of orofacial clefts in infants exposed to the mix drug during the primary trimester of pregnancy. Women of child-bearing age should have a bioassay before starting this drug and monthly thereafter. it’s also contraindicated in patients with hyperthyroidism, glaucoma, and in patients who have taken enzyme inhibitors within 14 days. Because topiramate can produce renal stones, this mix preparation should be used cautiously in patients with a history of renal stones.
Clinicians who prescribe and pharmacists who dispense the drug must be enrolled in an exceedingly Risk Evaluation and Mitigation Strategy, which incorporates a drugs guide, a patient brochure, and a proper educational program for prescribers, detailing safety information The initial dose of phentermine-topiramate is 3.75/23 mg for 14 days, followed by 7.5/46 mg thereafter. If after 12 weeks a 3 percent loss in baseline bodyweight isn’t achieved, the dose is increased to 11.25/69 mg for 14 days, and so to 15/92 mg daily If a private doesn’t lose 5 percent of weight after 12 weeks on the best dose, phentermine – topiramate should be discontinued gradually, as abrupt withdrawal of topiramate can cause seizures

We don’t recommend phentermine-topiramate for patients with upset (hypertension or coronary heart disease) or in pregnant women. Phentermine – topiramate could also be considered for obese postmenopausal women and men without disorder, particularly people who don’t tolerate orlistat or lorcaserin . Use of phentermine and topiramate individually is reviewed elsewhere.
Bupropion-naltrexone — the mixture of bupropion – naltrexone has also been evaluated in clinical trials. As an example, during a randomized trial of bupropion and an opioid-receptor antagonist, naltrexone (varying doses), versus double placebo, weight loss was greater in those assigned to active treatment (mean change in weight -5 to six percent versus -1.3 percent) Only 50 percent of participants completed 56 weeks of treatment. Nausea (30 versus 5 percent), headache (14 versus 9 percent), and constipation (15 versus 6 percent) occurred more frequently within the naltrexone-bupropion combination group. Although mean weight loss was greater with combination therapy than with placebo, mean reductions in pressure and pulse rate were significantly greater within the placebo group (-2.1/2.8 versus 0.2/-0.4 millimeter of mercury and -0.1 versus 1.5 beats per minute). this mixture isn’t commercially available. Use of bupropion alone is reviewed above


DIETARY SUPPLEMENTS

— Over-the-counter dietary supplements are widely employed by individuals attempting to slim down, but evidence to support their efficacy and safety are limited. samples of dietary supplements include ephedra (described above, not available), green tea, chromium, chitosan, and gum.
Guar gum preparations derived from the Indian Cyamopsis psoraloides are promoted as weight reduction agents. The presumed mechanism of action is a rise within the viscosity of gastric contents, resulting in a sense of postprandial fullness. However, in an exceedingly meta-analysis of 20 clinical trials, gum wasn’t effective for weight loss and caused adverse events like abdominal pain, flatulence, and diarrhea
Conclusions from a 2004 review of obtainable dietary supplements were as follows
• Chitosan and gum are ineffective for weight loss, and their use should be discouraged.
• Evidence and safety data are unclear for chromium, ginseng, glucomannan, green tea, hydroxycitric acid ], L-carnitine, psyllium, pyruvate supplements, St. John’s wort, and conjugated polyunsaturated fatty acid.
In a 2012 meta-analysis of trials comparing tea preparations with an effect in overweight or obese adults, tea leaf didn’t significantly affect weight loss or maintenance of weight loss
Hoodia gordonii, a dietary supplement derived from a xerophyte in Republic of South Africa, is marketed and sold as an drug. However, its efficacy and safety haven’t been established in clinical trials
Safety issues are a priority with dietary supplements. additionally to the issues with ephedra outlined above, a study of two weight loss preparations containing bitter orange (Citrus aurantium), a botanical source of synephrine, showed a non-dose related increase in pulse rate and blood pressure; the cardiovascular effects were postulated to relate to caffeine and other stimulants within the multicomponent formulations
Clinicians should caution patients about use of weight loss formulations and may monitor those that opt to use these supplements.
Compounded diet pills — Two compounded dietary supplements imported from Brazil, Emagrece Sim (also called the Brazilian diet pill) and Herbathin dietary supplement, are shown to contain pharmaceuticals, including amphetamines, benzodiazepines, and fluoxetine . In one report, 18 percent of Brazilian immigrant women were using these drugs while living within the United States; two-thirds reported adverse effects The US Food and Drug Administration has issued a warning against their use
Calcium — While epidemiologic data suggested that calcium supplementation could be related to weight loss a randomized, clinical test of 100 obese pre- and postmenopausal women undergoing a weight reduction program (with or without calcium supplementation 1000 mg/day), reported no significant effect of calcium on body fat or weight loss ]. Subsequent larger trials confirmed a scarcity of effect of calcium supplementation on weight

EXPERIMENTAL DRUGS

Peptides — There are several peptides that lead to weight loss, either by a discount in food intake or by increasing energy expenditure. None are currently approved by the FDA.
Leptin — Leptin could be a peptide produced primarily in fat. Absence of leptin is related to massive obesity in mice (ob/ob) and in humans In mice and rare humans with leptin deficiency, administration of physiological doses of leptin decreases food intake and causes weight loss In contrast, db/db mice and fatty rats, which have genetic defects within the leptin receptor and also are obese, don’t reply to leptin
Obese adults have leptin resistance, based upon the very fact that they need high serum leptin concentrations. during a study of 47 obese women and men given placebo or varying doses of recombinant human leptin for twenty-four weeks (and advised to eat 500 kcal but requirement each day), there was a weakly dose-dependent decrease in weight, starting from -1.3 kg within the placebo group to -1.4 kg within the 0.03 mg/kg group to -7.1 kg within the 0.30 mg/kg group These results suggest that leptin resistance may be overcome with high doses of leptin, but whether the effect will be sustained isn’t known. One small study suggests that leptin therapy may prevent regaining weight after significant weight loss by preventing the load loss-associated decrease in energy expenditure
Leptin therapy is effective in some patients with lipodystrophy.
Peptide YY — The gut hormone peptide YY (PYY) suppresses appetite and reduces food intake. This was illustrated during a trial of obese and lean adults receiving short-term intravenous PYY administration. Appetite and caloric intake decreased by approximately 30 percent in both groups, suggesting that PYY can be a useful therapy for weight loss
However, in a very 12-week trial of 133 obese patients who were randomly assigned to intranasal PYY (200 or 600 mcg thrice daily before meals) or placebo, in conjunction with diet and exercise, weight loss was similar within the placebo and 200 mcg PYY groups (2.8 and 3.7 kg, respectively) Weight loss couldn’t be assessed within the 600 mcg PYY group because 60 percent of patients dropped out because of nausea and vomiting.
Oxyntomodulin — Oxyntomodulin could be a peptide produced in L-cells of the GI track from the proglucagon gene product. When self-administered 3 times on a daily basis, half-hour before meals in obese volunteers, the group (n = 14) treated with oxyntomodulin lost 2.3 ± 0.4 kg compared with 0.5 ± 0.5 kg in those treated with placebo. Food intake was reduced by 250 kcal (35 ± 9 percent) within the last meal
Melanocortin-4 receptor agonists — The hypothalamic melanocortin system appears to play a vital role within the control of weight. As an example, intranasal administration of the melanocortin sequence MSH/ACTH4-10 to normal-weight subjects for 6 weeks decreased body fat by 1.7 kg ]. However, in a very study of 23 overweight men, the identical compound administered for 12 weeks didn’t induce any significant decrease in weight or body fat compared with placebo
Sympathomimetics

Tesofensine

— Tesofensine was initially developed for the treatment of encephalopathy. Although its efficacy was limited for this application, study participants lost a major amount of weight  it’s a presynaptic inhibitor of norepinephrine, dopamine, and serotonin. almost like sibutramine, it causes weight loss by suppressing appetite.
In a multi-dose dose-ranging trial, 203 obese patients were randomly assigned to tesofensine (0.25, 0.5, and 1.0 mg) or placebo once daily After 24 weeks, mean weight reduction was greater within the tesofensine groups (-6.7, -11.3, -12.8 kg, for the three doses, respectively) compared with placebo (-2.2 kg). Common adverse events included waterlessness, nausea, abdominal pain, and diarrhea. vital sign was significantly elevated altogether tesofensine groups (five to eight beats per minute). the best dose of tesofensine (1.0 mg daily) was related to a big increase in systolic and diastolic force per unit area (mean increase 6.8/5.8 mmHg).
The efficacy and safety of tesofensine require further investigation.

INFORMATION FOR PATIENTS

— UpToDate offers two forms of patient education materials, “The Basics” and “Beyond the fundamentals.” the fundamentals patient education pieces are written in plain language, at the 5 th to six th grade reading level, and that they answer the four or five key questions a patient may need a couple of given condition. These articles are best for patients who desire a general overview and preferring short, easy-to-read materials. Beyond the fundamentals patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the ten th to 12 th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to the present topic. We encourage you to print or e-mail these topics to your patients. (You also can locate patient education articles on a spread of subjects by searching on “patient info” and also the keyword(s) of interest
• Basics topics
• Beyond the fundamentals topics
SUMMARY and proposals
Diet and lifestyle
• All patients who are overweight (BMI ≥25 kg/m2) or obese (BMI ≥30 kg/m2) should receive counseling on diet, lifestyle, and goals for weight loss .)

Pharmacotherapy
• For individuals with a BMI >30 kg/m2 or a BMI of 27 to 29.9 kg/m2 with comorbidities, who have did not achieve weight loss goals through diet and exercise alone, we advise pharmacologic therapy be added to diet and exercise
• For obese patients, we recommend orlistat as first line pharmacologic therapy given its excellent cardiovascular safety profile and beneficial effects on serum total and cholesterin concentrations ). Treatment guidelines suggest up to 2 years of treatment. within the us, the Food and Drug Administration has approved orlistat for four years of use. However, if the patient has done well with weight loss/weight maintenance without adverse effects and desires to continue the drugs, we expect it’s reasonable to continue with an “informed consent” arrangement if both patient and clinician agree.

Lorcaserin is an alternate option for people who cannot tolerate orlistat. However, there are few long-term safety data. Lorcaserin should be discontinued if a patient doesn’t lose 5 percent of weight in 12 weeks.

Combination phentermine-topiramate is additionally an option for obese men or postmenopausal women without hypertension or coronary cardiovascular disease. for girls of child-bearing potential, a bioassay is required before initiating therapy and monthly thereafter since this mixture can produce fetal anomalies. If a patient doesn’t lose 5 percent of weight after 12 weeks on the very best dose, phentermine – topiramate should be discontinued gradually.
• For patients with type 2 diabetes, additionally to lifestyle modifications, we recommend initial therapy with metformin both for glycemic control and for modest weight reduction  we propose orlistat if further weight reduction is required
• For obese patients who are candidates for long-term pharmacotherapy for weight loss, we recommend not using sympathomimetic drugs ( phentermine , diethylpropion , benzphetamine , and phendimetrazine ) thanks to their potential for abuse
Bariatric surgery
• For patients with BMI ≥40 kg/m2 who have failed diet, exercise, and drug therapy, we propose bariatric surgery ( Grade 2B ). Individuals with BMI >35 kg/m2 with obesity-related comorbidities (hypertension, impaired glucose tolerance, DM, dyslipidemia, sleep apnea) who have failed diet, exercise, and drug therapy are potential surgical candidates, assuming that the anticipated benefits outweigh the prices, risks, and side effects of the procedure