OSTEOPOROSIS
Definitions
Osteoporosis is a generalized decrease in bone tissue mass even though the ratio of mineral (calcium and phosphorus) to organic elements (protein and collagen) is unchanged in the remaining morphologically normal bone.
It is defined by the World Health Organization (1991) as a systemic disease characterized by low bone mass and micro-architectural bone tissue deterioration, leading to enhanced bone fragility and increased fracture risk.
From a practical standpoint, osteoporosis is defined as a t score on a DEXA scan of less than -2.5. Osteopenia is defined as a t score between -1 and -2.5. This term was coined by the World Health Organization in 1992. The t score is a statistical measure which compares the bone density of the individual with the average bone density of a 20-29 year old female. The number actually refers to the number of standard deviations from the mean; it is not an absolute number. A t score of -1 signifies a 10% to 12% loss of bone mass.
The reason this number (the t score) is important is because it allows us to predict the risk of fracture. Bone density measurement predicts fracture risk as well as blood pressure measurement predicts stroke risk, and better than cholesterol level predicts heart attack risk - fracture risk is approximately doubled for each standard deviation decrement in bone density.
Primary osteoporosis (no identifiable cause) must be differentiated from secondary osteoporosis due to glandular problems such as hyperparathyroidism, Cushing's syndrome, hypogonadism, and hyperthyroidism; cancer such as multiple myeloma; and gastrointestinal problems such as celiac disease, and malabsorption. Blood tests (PTH, TSH, dexamethasone suppression, testosterone, SPEP), stool tests (fecal fat), and urine tests (24 hour calcium) can all be helpful in distinguishing primary from secondary osteoporosis. Suspect secondary osteoporosis if the Z score, which compares the bone density of the individual to the bone density of a healthy age and sex matched control, is less than -2.
Osteomalacia, a much rarer disease caused by defective calcification of bone, also causes decreased bone density. Osteomalacia causes soft bone; osteoporosis causes brittle bone. These two conditions can be definitively differentiated only by a bone biopsy, but abnormal blood tests (i.e. calcium, phosphorous, alkaline phosphatase, 25 hydroxy vitamin D) can point toward a diagnosis of osteomalacia. Even though the interpretation of a DEXA scan refers to osteoporosis when the bone density is low, the DEXA scan cannot actually differentiate between osteomalacia and osteoporosis.
Bone is morphologically divided into trabecular (cancellous) bone and cortical (compact) bone. Trabecular bone is more metabolically active and therefore estrogen deficiency leads to more rapid loss. 80-85% of the skeleton is cortical bone. The spine is 65-75% trabecular bone, the heel is >75% trabecular bone, but the hip is only 25-50% trabecular bone, and the wrist is only 25% trabecular bone.
The staggering statistics (in the U.S.)
Based on NHANES III (1988 - 1994) DEXA data and the most recent census data, there are 4 - 6 million women and 1 - 2 million men with osteoporosis, and 13 - 17 million women and 4 - 9 million men with osteopenia. In women over age 50, these numbers translate into prevalence statistics of 13% to 18% of women over age 50 with osteoporosis and up to 50% with osteopenia (J Bone Miner Res. 1997. 12. 1761-1768 as cited in Arch Intern Med. 2004. 164. 1047-1048).
By 2020 it is estimated that 12.3 million individuals in the US older than 50 will have osteoporosis (JAMA. 2018. 319. 2521-2531).
Primary osteoporosis affects 1 in 4 women over age 65.
1,200,000 fractures/year are attributed to osteoporosis.
25% of women over age 50 will sustain a vertebral compression fracture. 80% are associated with acute pain.
1/3 of women and 1/6 of men over age 65 will sustain a hip fracture. 24% 1 year mortality (Mayo Clin Proc. 2001. 76. 295-298). Annual death toll is 50,000.
At age 50, a white woman has a 40% lifetime chance of experiencing a fracture related to decreased bone mass (J Bone Miner Res. 1992. 7. 1005-1010); the lifetime risk of hip fracture is 17% (Osteoporos Int. 1992. 2. 285-289).
Each year in the United States, there are approximately 250,000 hip fractures, 240,000 wrist fractures, and 500,000 vertebral compression fractures – the cost of treating osteoporotic fractures in the U.S. in 2005 estimated at $16.9 billion/year.
One in five patients with a hip fracture dies within a year of the fracture, and 50% fail to regain prefracture mobility and independence.
For women, the lifetime risk of dying of hip fracture is the same as the lifetime risk of dying of breast cancer.
Men over age 50 are at greater risk for osteoporosis-related fracture than they are for prostate cancer.
Osteoporosis-related disability in one study in Switzerland was associated with more inactive days in bed than stroke, myocardial infarction, breast cancer, or COPD.
Other pertinent statistics (Cleve Clinic J Med. 2002. 69. 964-976)
Aging has a marked effect on the risk of falls; the yearly risk increases from 1 in 5 in the 60-64 age bracket to 1 in 3 in the 80-84 age bracket.
NHANES III found that "only" 42% of women age 80-84 have a t score lower than -2.5 in the femoral neck - osteoporosis is thus not ubiquitous in this age group.
Celiac disease is present in as many as 10% of premenopausal women with idiopathic osteoporosis, based on a report in which 10.1% of 89 premenopausal women tested positive for celiac disease by antiendomesial antibody testing (Clin Rheumatol. 2005. 24. 239-243).
The contribution of low bone mass to hip fracture risk declines with age as the contribution of falls increases
Data from the Rotterdam study indicate that the risk of hip fracture in a 58 year old with a femoral neck bone density of 0.5 g/cm2 has a one year risk for hip fracture of 0.5% whereas a 90 year old with the same bone density has a one year risk of hip fracture of 5%.
In patients younger than age 65 in the lowest quartile of Singh grade (i.e. the most osteoporotic), the risk of hip fracture is 33 times the risk in the least osteoporotic patients; over age 85 the most osteoporotic are at only 5 times the risk of the least osteoporotic.
Only about half of all hip fractures occur in patients with t scores lower than -2.5.
Bisphosphonate medications are most effective at preventing hip fractures in the subset of women with osteoporosis and previous vertebral compression fractures.
Other pertinent information
Data (i.e. autopsy data) would indicate that osteoporosis is a 20th Century phenomenon.
Bone is dynamic, living tissue, composed of an organic component as well as an inorganic component.
Mineral crystals known as hydroxyappetites make up about 1/2 – 2/3 of bone mass.
The remaining 1/3 – 1/2 of bone mass consists of living cells and type 1 collagen fibers (derived from protein) that form a matrix referred to as ‘ground substance.’
Bone is constantly remodeling and repairing microscopic damage. 25% of trabecular bone and 3% of cortical bone is remodeled annually.
Osteoblasts make new bone and osteoclasts cause bone resorption.
Osteoblasts make new bone and osteoclasts cause bone resorption.
Osteoporosis occurs when bone resorption exceeds bone formation (most of the time, we don't understand why this happens).
Bone loss averages 1% per year after age 35; increased to 2% per year for 5-10 years after menopause.
Vitamin and mineral intake from our food is likely much less than it was a century ago in well nourished individuals
Refined grains have far less vitamins and minerals than whole grains.
Current farming techniques deplete the soil of many key minerals.
Food preservatives such as EDTA may interfere with absorption of vitamins and minerals.
Industrial chemicals such as hydrazines and hydrazides can interfere with metabolism of vitamins and minerals.
Screening Guidelines - United States Preventive Services Task Force (USPSTF) 2018 (JAMA. 2018. 319. 2521-2531).
This is an update of the 2011 guideline.
USPSTF recommends screening for osteoporosis with bone mineral density measurement in women 65 years and older (B recommendation)
USPSTF recommends screening for osteoporosis with bone mineral density measurement in women younger than 65 years old who are at increased risk for osteoporosis, as determined by a formal risk assessment tool, including FRAX, SCORE, and OST (B recommendation).
USPSTF concludes that evidence is insufficient to balance benefits and harms of osteoporosis screening in men (I statement).
Guidelines pertaining to serial DEXA scans (JAMA Insights. JAMA. 2021. 326. 1622-1623)
Change in BMD over time can only be reliably interpreted if serial DEXA measurements occur on the same BMD machine (or if there is formal cross-calibration between the machines).
Typical DEXA measurement variability is 3% - 6%, which markedly exceeds the average rate of BMD loss, which is typically 0.5% - 1 %/year.
Optimal frequency of serial BMD measurement should be based on baseline BMD and consideration of new risk factors for fracture or BMD loss - in individuals age 65 or older who have normal BMD, progression to osteoporotic BMD or treatment-level fracture risk is likely to take more than 10 years, and thus there is no need to repeat DEXA scans every 2-3 years in this subpopulation.
Treatment Guidelines (Clinical Guideline published in Annals of Internal Medicine. 2017. 166. 818-839 and editorial 852-853)
ACP recommends that clinicians offer pharmacological treatment with 1 of 3 bisphosphonates or denosumab to women with known osteoporosis. STRONG
ACP recommends that clinicians treat osteoporotic women with pharmacologic therapy for 5 years. WEAK
ACP recommends that clinicians offer pharmacological treatment with bisphosphonates to men who have clinically recognized osteoporosis. WEAK
ACP recommends against bone density monitoring during the 5-year pharmacologic treatment period in women. WEAK
ACP recommends against using hormone replacement therapy or raloxifene to treat osteoporosis in women. STRONG
ACP recommends individualization of treatment in women over age 65 with osteopenia. WEAK
Unanswered questions
Ann Intern Med. 2004. 140. 153-156
While bone density clearly predicts fracture risk in untreated patients, it is unclear whether it predicts fracture risk in treated patients. Bone density is a surrogate marker for bone strength, and available data suggests that current pharmacologic treatments have similar effects on vertebral fracture reduction independent of their effects on bone density. HOWEVER, data from a registry-based cohort study show that, as compared with stable total hip bone mineral density, increases in bone density with treatment are associated with a reduced fracture risk, and decreases in bone density are associated with an increased fracture risk (Ann Intern Med. 2016. 165. 465-472).
Unclear for how long to continue treatment and whether long-term pharmacologic treatment may in fact have risks which exceed benefits.
Unclear for how long reductions in fracture risk persist after discontinuation of pharmacologic treatment.
Am J Med. 2008. 121. 744-747
Mechanism of action of bisphosphonates is incompletely understood
Mathematical modeling indicates that only 16-28% of preventative action of alendronate and risendronate against fractures is attributable to the increase in bone mineral density (Stat Med. 2001. 20. 3175-3188).
This means that weekly or monthly administration of bisphosphonates may not be as effective at reducing fractures as daily administration, because the available data on weekly or monthly administration uses BMD as a surrogate endpoint.
As of 2008, there are no comparative studies of the effectiveness of the various bisphosphonates.
If a fracture occurs after 6 months on a given pharmacologic treatment, no data on whether the pharmacologic agent should be changed.
There is no data on whether combination treatments are more effective than monotherapy.
The effect of treatment with strontium ranelate or bisphosphonates on subsequent treatment is unknown.
Still unclear for how long reductions in fracture risk persist after discontinuation of pharmacologic treatment (i.e. therapeutic window).
There is no data on safety and efficacy after more than 10 years of pharmacologic treatment.
Risk factors for osteoporosis
Aging
Being thin
Cannabis use (heavy), based on cross sectional data (Am J Med. 2017. 130.214-221).
Chronic kidney disease - an eGFR < 60 mL/min is associated with a doubling of the risk of osteoporosis (J Am Soc Nephrol. 20016. 17. 3223-3232).
Comorbidities: AIDS, amyloidosis, ankylosing spondylitis, anorexia nervosa, celiac disease, cirrhosis, COPD, depression (Arch Intern Med. 2007. 167. 2329-2236), hemochromatosis, hepatitis (chronic), inflammatory bowel disease, mastocytosis, multiple myeloma, multiple sclerosis, rheumatoid arthritis, SLE, and stroke.
Endocrine influences: decreased levels of estrogen or testosterone (i.e. hypogonadism), hyperthyroidism, Cushing’s syndrome, hyperparathyroidism.
Genetic influences: Asian, Caucasian, female, family history, osteogenesis imperfecta, homocysteinuria, Marfan’s syndrome
Joint hypermobility syndrome - RR of 1.8 (Clin Rheumatol. 2006. 25. 511-514).
Lifestyle: immobility, cigarette smoking
Medications: aluminum containing antacids, anticonvulsants, aromatase inhibitors, cytotoxic drugs, estrogen-blockers (i.e. medroxyprogesterone acetate injection for endometriosis, tamoxifen), furosemide (Lasix), glucocorticoids, GnRH agonists, heparin, immunosuppressants, lithium, proton pump inhibitors, SSRI and SNRI medications, thiazide diuretics, thiazolidinediones (TZDs), and thyroid replacement (supra-physiologic doses).
Nutrition: low calcium intake, low protein intake, excessive alcohol intake, excessive caffeine intake, excess (synthetic) vitamin A intake, possibly excessive soda intake (phosphoric acid), malabsorption, vitamin D deficiency.
High homocysteine
The hypothesis that homocysteine may be a risk factor was suggested by data showing that individuals with homozygous homocystinuria have a high incidence of osteoporosis and premature fractures (Am J Hum Genet. 1985. 37. 1-31).
From a mechanistic standpoint, homocysteine inhibits collagen cross linking (Biochim Boiphys Acta. 1996. 1315. 159-162) and impairs bone mineralization (Bone. 2001. 28. 387-398).
Large epidemiologic studies in elderly men and women show a correlation between elevated homocysteine and osteoporotic fractures, independent of bone mineral density (N Engl J Med. 2004. 350. 2033-2041; N Engl J Med. 2004. 350. 2042-2049).
Common variant in the MTHFR gene (which leads to increased homocysteine levels) is associated with lower bone mineral density and increased fracture risk in postmenopausal women (Calcif Tissue Int. 2000. 66. 190-194; J Bone Miner Res. 2003. 18. 723-9).
Reduction in hip fracture risk following stroke in the group treated with vitamin B12 1.5 mg daily and folate 5 mg daily suggests that elevated homocysteine is causally related to osteoporosis. This study was conducted in 628 elderly Japanese with residual hemiplegia, and the number of hip fractures per 1000 patient years was reduced from 43 in the control group to 10 in the treatment group. This represents a 7.1% absolute decrease in risk of hip fracture, for a number needed to treat of 14 to prevent one hip fracture (JAMA. 2005. 293. 1082-1088). However, concerns about scientific misconduct cast doubts on the validity of the results (JAMA. 2015. 313. 1914).
Negative intervention trial: In B-PROOF, a 2-year RCT of 2919 individuals aged 65 and older, with an elevated homocysteine level (12-50 micromol/L), folate 400 mcg daily plus vitamin B12 500 mcg daily, there was a nonsignificant decrease in fracture risk of 16%. However, in a prespecified subgroup analysis of participants over age 80, there was a significant 70% decrease in risk of osteoporotic fracture (p<0.02) [Am J Clin Nutr. 2014. 100. 1578-1586].
Systemic inflammation
Inflammation causes bone resorption (i.e. arthritis, periodontal disease).
Diseases with inflammatory components, such as rheumatoid arthritis, Crohn’s disease and multiple sclerosis appear to be independent risk factors for osteoporosis.
Trends toward greater spinal bone loss were observed in women with high cytokine production (Calcified Tissue Int. 1998. 63).
In women more than 10 years post menopause, IL-6 levels predicted femoral bone loss (J Clin Endocrinol Metab. 2001. 86. 2032-2042).
Decreased estrogen leads to increased inflammatory cytokines and decreased bone density (J Endocrinol Invest. 2002. 25. 684-690).
There is preliminary data that omega 3 fatty acids have a beneficial effect on bone metabolism via modulation of osteoblast function (Prostaglandins, Leukotrienes, and Essential Fatty Acids. 2003. 68. 397-398).
A review article of “Effects of Rheumatoid Arthritis on Bone” concludes that “Recent studies have strengthened the evidence that inflammation and immobilization are strong risk factors for the twofold increase in …osteoporosis seen in…patients with rheumatoid arthritis” (Curr Opin Rheumatol. 2003. 70. 257-262).
“Gene targeting studies have shown that the transcription factor nuclear factor kB (NF-kB) has a crucial role in osteoclast differentiation..” and in vivo studies with a cell-permeable inhibitor of the NF-kB kinase complex show that “…selective inhibition of NF-kB activation offers an effective therapeutic approach for inhibiting chronic inflammatory diseases involving bone resorption” (Nature Medicine. 2004. 10. 417-422).
Activation of RANKL (the receptor activator of NF-kB ligand) increases bone loss (JAMA. 2004. 292. 490-495).
“Accumulating evidence shows that (osteoporosis and CVD) are both part of the same pathological process associated with increased systemic inflammation” (Endocrine. 2004. 23. 1-10).
Low antioxidant status
Mechanism - free radicals are used by osteoclasts to “chisel away at older bone” and excess free radicals can thus lead to excess bone resorption (Clin Chim Acta. 2002. 318. 145-148).
Low levels of plasma antioxidants correlated with increased osteoporotic risk in a cross sectional study (J Clin Endocrinol Metab. 2003. 88. 1523-1527).
Dietary lycopene with vitamin C > 500 mg/day reduces oxidative stress based on serum markers and decreases bone turnover (Presentation at 2005 Meeting of the American Society for Bone and Mineral Research).
Exposure to certain heavy metals, including aluminum, cadmium, lead, and tin.
Aluminum is present in many antacids, cookware, beverage cans, and some tap water supplies. Aluminum soda cans are probably a worse culprit than aluminum beer cans because the acidity of the soda is likely to cause more aluminum from the can to dissolve in the beverage.
Cadmium is present in cigarette smoke, motor oil, tires, galvanized parts of motor vehicles, and is used in the manufacturing of batteries, fertilizers, paints, plastics, textiles, and children’s jewelry imported from China. Small quantities may be found in various foods, grains, leafy vegetables, peanuts, potatoes, soybeans, spinach, shellfish from coastal waters contaminated with cadmium, and sunflower seeds. Note foods grown using high-phosphate fertilizers will have cadmium as there are small amounts of cadmium in the fertilizer.
A study in 2688 women in Sweden found that women with urinary cadmium levels > 0.75 mcg/g creatinine had a 245% increased risk of osteoporosis at the femoral neck and a 197% increased risk of osteoporosis at in the lumbar spine, compared with women with urinary cadmium levels < 0.50 mcg/g creatinine (J Bone Miner Res. 2011. 26. 486-495).
In another study, women with urinary cadmium between 0.50 and 1.00 mcg/g creatinine had a 43% greater risk for osteoporosis of the hip as compared with women with urinary cadmium levels < 0.50 mcg/g creatinine (Bone. 2012. 50. 1372-1378).
Mechanisms by which cadmium disrupts bone metabolism include damaging osteoblasts, stimulating osteoclasts and impairing kidney function (and this interferes with conversion in the kidney of 25 OH vitamin D to 1, 25 dihydroxy vitamin D).
Lead remains ubiquitous in our environment, despite the elimination of leaded gasoline and reduced use of lead paint.
90% of the body burden of lead is in the bones.
Lead levels correlate inversely with bone density (Bone. 2015. 79. 58-64).
Mechanisms by which lead disrupts bone metabolism include damaging osteoblasts, stimulating osteoclasts and impairing kidney function (and this interferes with conversion in the kidney of 25 OH vitamin D to 1, 25 dihydroxy vitamin D).
Tin is present in tin cans for food and beverages, some fungicides and insecticides, some chemical preservatives (stannous chloride) and some toothpastes (stannous fluoride).
Pesticides- organophosphate and organochlorine pesticides can cause chronic kidney disease, which increases the risk of osteoporosis.
Plasticizers - cause inflammation and disrupt endocrine system function
Phthalates - women with higher urine levels have a higher risk of osteoporosis (J Clin Endocrinol Metab. 2014. 99. E1997-E2003).
Bisphenol A - directly suppresses both osteoblast and osteoclast activity, and thus interferes with bone renewal.
Excess fluoridation of the water supply – a study of 3777 individuals living in 75 different parishes in southwestern France showed that the risk of hip fracture was 86% higher when water fluoride level was above the median (0.11 mg/liter), as compared to the group in which the water fluoride level was below the median (JAMA. 1995. 273. 775-776).
Probably acid rain exposure
Acid rain increases the acidity of our drinking water. Calcium may be leached from the bone to buffer acidity in the bloodstream.
Toxic metals (aluminum, cadmium, lead) are released from rocks, eventually entering the soil or drinking water supply.
Lead from plumbing may be released into drinking water supply by acidic water in pipes.
Probably food sensitivities – celiac disease is a risk factor for osteoporosis; a gluten free diet is associated with reversal of osteoporosis.
Possibly a meat and grain based diet which increases acidity as these foods are metabolized – calcium may be pulled from the bone to neutralize the pH in the bloodstream.
Possibly hypochlorhydria – Dr. Jonathan Wright has observed that hypochlorhydria is common in osteoporosis, using Heidelberg testing to establish a diagnosis of hypochlorhydria. A small clinical trial in 42 young adults with “alveolar bone resorption” and 37 controls found decreased acidity by gastric analysis in those with bone resorption (Proc Soc Exp Biol Med. 1941. 48. 98).
Diagnosis of low bone density
X ray: 20-30% bone loss is necessary before X rays show osteopenia, so X rays are not very sensitive.
Dental X rays: Mandibular inferior cortical shape on dental panoramic X rays may be an indicator of bone turnover, with sensitivity and specificity not currently known (J Bone Mineral Res. 2003. 210. 1689).
Bone mineral density measurement is definitive (bone densitometry was invented by dentists in 1897)
Single photon absorptiometry - measures bone density at the wrist. This is not very useful because this does not correlate well with hip fracture or vertebral compression fracture risk.
Dual photon absorptiometry - measures bone density at the hip. This is a 20 minute test which costs $150-$250. The radiation exposure is less than that associated with a chest X ray, about 1/10 of the average yearly total environmental exposure.
Quantitative CT - good measure, but 50-75 times the radiation exposure of dual photon absorptiometry.
Dual energy X ray absorptiometry (DEXA) - less expensive than dual photon absorptiometry ($100-$150), and scan time is only 5-10 minutes. This is the diagnostic test of choice. This came into widespread use in the 1980s.
Note this is a stronger predictor of fracture risk in white women than African American women, based on a prospective cohort study in 7334 white women and 636 African American women with 6.1 years of follow up (JAMA. 2005. 293. 2102-2108).
Note that African American women have a 30-40% lower fracture risk than white women at every level of bone mineral density, based on a prospective cohort study in 7334 white women and 636 African American women with 6.1 years of follow up (JAMA. 2005. 293. 2102-2108).
Ultrasound of the calcaneus.
CT of the abdomen – a cross sectional cohort study determined that “Abdominal CT images obtained for other reasons that include the lumbar spine can be used to identify patients with osteoporosis or normal BMD without additional radiation exposure or cost” (Ann Intern Med. 2013. 158. 588-595).
Do the test only if it will change treatment.
OST index: 0.2 x (weight in kilograms - age in years). If value is 2 or higher, no need to do DEXA scan.
USPSTF guidelines - screen women at age 65 in the absence of risk factors, at the age of 60 with risk factors.
Medicare does cover the cost of a screening DEXA in women as of 2002.
Relationship between low bone mineral density and fractures
Bone density is a strong predictor of fracture risk, just as hypertension is a predictor of stroke risk and just as high cholesterol is a predictor of MI risk.
However, the majority of fractures occur in individuals without osteoporosis by bone mineral density measurement (i.e. T score < -2.5).
In a longitudinal observational study in which bone mineral density tests were conducted at peripheral sites in postmenopausal women, at 12 months of follow up, 82% of women who reported a fracture of the wrist, forearm, hip, rib, or spine had a T score < -2.5, and 67% has a T score < -2.0 (Arch Intern Med. 2004. 164, 1108-1112).
A study examining the 10 year risk of a fracture of the hip, spine, forearm, or proximal humerus in a 50 year old woman concluded that at 10 years, 96% of all fractures in these locations will occur in women with a T score < -2.5 (Bone. 2002. 30. 251-258).
The North American Menopause Society (NAMS) in a 2006 position statement concluded that “fracture risk depends largely on factors other than BMD” (Menopause. 2006. 13. 340-367).
Determine the approximate risk of hip fracture at https://www.sheffield.ac.uk/FRAX/tool.aspx?country=9
Osteoporosis treatment
Conventional prescription medications: N0TE bisphosphonates are typically taken for only 5-7 years; anabolic medications are typically taken for only 1-2 years (due to an increased risk of bone cancer with long term use) with bisphosphonates typically prescribed following a course of treatment with anabolic medications.
Abaloparatide (Tymlos®) - PTHrP(1–34) analog that acts as an agonist at the PTH1 receptor. It activates the cAMP signaling pathway, which triggers the remodeling process to increase bone formation.
Bisphosphonates (alendronate/Fosomax®, risedronate/Actonel®, ibandronate/Boniva®) - slow the breakdown of bone, but do not build bone
Calcitonin (subcutaneous injections or nasal spray/Miacalcin®). NOTE calcitonin sometimes provides significant symptom relief from the pain associated with a vertebral compression fracture
Denosumab/Prolia® - biologic therapy
Human recombinant parathyroid hormone analogues (teriparatide/Forteo®) - increases bone formation and reduces fracture risk, for both vertebral and nonvertebral fractures.
Monoclonal antisclerostin antibody (romosozumab/Evenity®) - increases bone formation and decreases bone resorption
SERMs - (raloxifene/Evista®, abaloparatide/Tymlos®)
NOTE neither calcium nor estrogen significantly reverses established osteoporosis.
Alkalinization of the urine (beware of risk if chronic kidney disease)
In a RCT in 161 women with osteopenia, oral potassium citrate, 30 mEq/day, which produced systemic alkalinization, led to significant improvements in bone mineral density (J Am Soc Nephrol. 2006. 17. 3212-3222).
Supplementation with potassium and magnesium citrate associated in a RCT with decreased urinary excretion of calcium, increased bone density, and decreased fracture (J Clin Endocrinol Metab. 2013. 98. 207-217).
Osteoporosis prevention/treatment
Environmental measures
Avoid excess fluoridation of the water supply – a study of 3777 individuals living in 75 different parishes in southwestern France showed that the risk of hip fracture was 86% higher when water fluoride level was above the median (0.11 mg/liter), as compared to the group in which the water fluoride level was below the median (JAMA. 1995. 273. 775-776).
Avoid exposure to acid rain, if possible
Eat organic as much as possible, as there is some data that nutrient value of organic food is superior to nutrient value of non-organic food.
Limit exposure to toxic metals and other environmental toxins/consider “detoxification” measures (see section above on this page on “Risk Factors”)
Lifestyle measures
Alcohol in moderation – 1-2 alcoholic beverages per day
Exercise - see separate section just below
Nutrition - see separate section below
Smoking cessation
Exercise - UK Consensus Statement (based on published evidence) recommends that “people with osteoporosis should undertake resistance and impact exercise to improve bone strength and balance…” (Br J Sports Med. 2022. 56. 837-846)
Weight bearing exercise
Walking one mile/day reduces rate of bone loss; it is unclear how much extra benefit is derived from strenuous exercise.
In a RCT in 246 women age > 65, those assigned to the 18 month exercise program showed significantly improved bone mineral density and a reduced fall risk (Arch Intern Med. 2010. 170. 179-185).
Extended follow up, mean of 7.1 years, in 160 women, aged 70-73 at baseline, enrolled in a RCT of a home exercise program showed that showed that “home-based exercises followed by voluntary home training seem to have a long-term (beneficial) effect on balance and gait, and may even protect high-risk elderly women from hip fractures” (Arch Intern Med. 2010. 170. 1548-1556).
NOTE too much exercise (i.e. enough to cause amenorrhea, which is the loss of menstrual periods) increases the risk of osteoporosis in pre-menopausal females
Weight training
Theoretically beneficial based upon increases muscle mass, so a fracture is less likely with a fall, and improves balance so that falling is less likely to occur.
HOWEVER, in a RCT of 2157 adults aged 70 years or older, a strength-training exercise program of 30 minutes 3 times per week did not affect the incidence of nonvertebral fractures at 3 years of follow-up (JAMA. 2020. 324. 1855-1868).
Nutrition
Caffeine – limit intake to 2-6 caffeinated beverages per day
NOTE adequate calcium intake may protect against caffeine-induced bone loss (Am J Clin Nutr. 1994. 60. 573-578).
NOTE black/green/oolong tea may be protective against osteoporosis, based on epidemiological data.
Dairy - limit intake
Despite the advertisements for milk for osteoporosis prevention, epidemiologic and cross cultural data actually show a positive correlation between intake of milk products and osteoporotic fractures (Hippocrates. July/August 1999. 53-55).
A 12 year Harvard study which prospectively tracked the dietary intake and medical histories of 77,761 women showed an increased risk of osteoporotic fractures associated with increased milk consumption (Am J Pub Health. 1997. 87. 992-997).
In a review of 37 studies of dairy or unsupplemented dietary calcium intake in children, adolescents, and young adults, 27 studies found no relationship between dairy or dietary calcium intake and measures of bone health (Pediatrics. 2005. 115. 736-743).
Fiber – fiber intake is good for health in general, but beware excess fiber intake may increase fecal elimination of calcium.
Lycopene – plentiful intake; dietary lycopene intake may function synergistically with vitamin C to reduce bone turnover (Presentation at 2005 Meeting of the American Society for Bone and Mineral Research).
Protein – moderate intake. Despite conventional wisdom that high dietary protein intake can increase urinary calcium losses and theoretically increase the risk of osteoporosis (calcium balance is detrimentally affected by an increased intake of purified proteins), published data would suggest that it is actually low protein intake, which is associated with inadequate intake of phosphorous, which can increase the risk of osteoporosis.
A 4 year study examining changes in bone density in 391 women and 224 men from the population-based Framingham Osteoporosis Study. Even after controlling for known confounders including weight loss, women and men with relatively lower protein intake had increased bone loss, suggesting that protein intake is important in maintaining bone or minimizing bone loss in elderly persons. Further, higher intake of animal protein does not appear to affect the skeleton adversely in this elderly population. In this study, usual dietary protein intake was determined using a semiquantitative food frequency questionnaire (FFQ) and expressed as percent of energy from protein intake (J Bone Miner Res. 2000. 15. 2504-2512).
A study in thirty-two subjects with usual protein intakes of less than 0.85 g/kg/day who were randomly assigned to daily high (0.75 g/kg) or low (0.04 g/kg) protein supplement groups found that changes in urinary calcium excretion in the two groups did not differ significantly over the course of the study. Furthermore, the high protein group had significantly higher levels of serum IGF-I (a bone growth factor) and lower levels of urinary N-telopeptide (a marker of bone resorption). In this study, Isocaloric diets were maintained by advising subjects to reduce their intake of carbohydrates (J Clin Endodrinol Metab. 2004. 89. 1169-1173).
In a study in 15 healthy postmenopausal women who consumed diets with similar calcium content (approximately 600 mg), but either low or high in meat (12 vs. 20% of energy as protein) for 8 week each, in a randomized crossover design, a high meat compared with a low meat diet for 8 week did not affect calcium retention or biomarkers of bone metabolism (J Nutr. 2003. 133. 1020-1026).
The type of protein consumed may be very important - women with a higher animal protein intake have a greater 7-y rate of bone loss at the femoral neck (p=0.02) and an adjusted RR of 3.7 for fracture (p=0.04) v. women with high vegetable protein intake (Sellmeyer DE et al. Am J Clin Nutr. 2001. 73. 118).
Prunes (dried plums) - consumption of 50 grams per day and 100 grams per day associated with less total body bone loss, in a 6 month RCT of 48 women with osteopenia (Hooshmand S et al. Osteoporosis Int. Epub 2/22/16).
Salt – limit intake; sodium induces increased urine excretion of calcium
Soy- a 4 ½ year prospective cohort study looking at the relationship between usual soy food consumption and fracture incidence in 74,942 women aged 40-70 found a statistically significant inverse relationship between soy consumption and bone fractures; the relationship also showed a dose-response relationship across quintiles of soy intake (Arch Intern Med. 2005. 165. 1890-1895).
Sugar – limit intake; sugar ingestion may deplete our bodies of calcium and raise cortisol levels
Vegetarian diet - conflicting data, with some epidemiologic data shows that vegetarians have increased bone density, but a study showing a 33% higher risk of hip fracture in vegetarians as compared with meat or fish-eaters (BMC Medicine. August 11, 2022).
Complementary modalities of treatment
Tai chi
Reduces the risk of falling
Reduces the risk of falling in the elderly by 47.5%, based on a RCT in 200 subjects over age 70, in which treatment subjects met with an instructor twice a week for 20 minutes, and were encouraged to practice on their own for 15 minutes twice a day (J Am Geriatr Soc. 1996. 44. 489). This study in 2003 was named by the American Geriatric Society as the best research paper from the 1990’s, and was republished (J Am Geriatr Soc. 2003. 51. 1794-1803).
Reduces the risk of falling in the elderly, based on a RCT in 256 physically inactive subjects over age 70. The treatment group attended one hour classes 3 times a week for 6 months, and those in the tai chi group had 55% fewer falls (p=0.007). Repeat assessment 6 months after completion of the study showed that group differences with regard to falls persisted (p<0.001) [J Gerontol A Biol Sci Med Sci. 2005. 60. 187-194].
Reduces the number of falls among healthy elderly, based on aggregate data from 5 RCTs (Altern Ther Health Med. 2011. 17[1]. 40-48).
Improves balance in older adults, based upon data from 13 RCTs (Altern Ther Health Med. 2011. 17[1]. 40-48).
Tai Chi and prevention of osteoporosis – data is mixed
A review of controlled studies concludes that tai chi may be a method of maintaining bone density in postmenopausal women (Arch Phys Med Rehab. 2007. 88. 673-680).
A systematic review article of 5 RCTs and 2 controlled clinical trials concludes that clinical trial data is not convincing with regard to showing benefit (Osteoporosis Int. 2008. 19. 139-146).
Reduced rate of bone loss was seen in one study - a 12 month RCT in 132 postmenopausal Chinese women who practiced tai chi an average of 4.2 times per week. There were also fewer fractures in the tai chi group, possibly due to fewer falls from improved balance (Arch Phys Med Rehab. 2004. 85. 717-722).
For more information on tai chi, go to the Complementary Modalities page of this website and scroll to near the bottom.
Whole body vibration (Self Healing. 8/09. Pg. 4)
These machines in 2009 are in some health clubs and available for home purchase (cost ranging from a few hundred dollars to a few thousand dollars) look similar to a treadmill, but in place of a moving belt is a platform that oscillates at a calibrated frequency between 5 and 45 Hz.
Mechanism of action uncertain in 2009; some published data showing use is associated with increased bone density, increased muscle strength and improved balance.
May be a good alternative to aerobic exercise and weight training for older individuals or those with functional limitations interfering with ability to exercise or weight train.
Yoga - BEWARE certain poses such as the bridge pose can increase the risk of bone or joint injuries (Mayo Clin Proc. 2019. 94. 385-387).
Medications
Thiazide diuretics - evidence is conflicting, with theoretical mechanisms of benefit and harm (thiazide diuretics decrease calciuria, but they may induce hyponatremia, which has been associated with an increased risk of vertebral fractures).
Several epidemiologic studies and a prospective cohort study show benefit (Ann Intern Med. 2003. 139. 476-482).
Prospective data in 55,780 women participating in the Nurses' Health Study show that "Thiazide diuretics and loop diuretics are each independently associated with increased risk of vertebral fracture in women" (Am J Med. 2016. 129. 1299-1306).
Beta-blockers based on animal data and a case control study (JAMA. 2004. 292. 1326-1332).
Hormones
Estrogen - effectiveness of estrogen well documented in controlled clinical trials, but based upon the WHI (Women’s Health Initiative) data on harms, risk generally outweighs benefit for the indication of osteoporosis prevention.
Low dose estrogen may be an option for which the risk/benefit ratio is acceptable – in one 3 year trial, 0.25 mg/day of 17-beta-estradiol (1/4 of the standard dose) was associated with increased bone density of the hip, spine, and total body (JAMA. 2003. 290. 1042-1048).
For full details on risks and benefits of estrogen, return to Home Page and click on Menopause.
Progesterone
Most trials of progesterone have used estrogen plus progesterone together.
Dr. John Lee has published data on improvement in BMD in 100 women using a 3% progesterone cream 12 consecutive nights per month for 3 years (Int Clin Nutr Rev. 1990. 10. 384-391; Med Hypotheses. 1991. 35. 316-318). His positive results have not been replicated.
NEGATIVE study – a RCT of 102 women within 5 years of menopause, using 20 mg of topical progesterone daily. After 1 year, bone mineral density (BMD) of the lumbar spine and hip were equal in the placebo group and the topical progesterone group (Obstet Gynecol. 1999. 94. 225-228).
Testosterone
May be beneficial in men on prescription corticosteroids, based on a trial in 15 asthmatics (Arch Intern Med. 1996. 156. 1173-1177).
May be beneficial in men with low free testosterone serum levels, based one trial in 36 men ((J Clin Endocrinol Metab. 1996. 81. 4358-4365) and another trial in 48 men (J ClinEndocrinol Metab. 2004. 89. 503-510).
Risks of treatment with testosterone are not well defined.
DHEA – well tolerated in various clinical trials, but risks are not well defined, especially with regard to men and women with hormone dependent conditions (BPH, prostate cancer, endometriosis, fibroids, breast cancer, ovarian cancer) [Alt Med Alert. 2007. 10. 13-17].
Several small trials of DHEA in women have shown a beneficial effect on BMD, without an adverse effect on the endometrium (J Clin Endocrinol Metab. 1997. 82. 3498-3505; J Endocrinol. 1996. 150. S43-S50).
Controlled clinical trials have shown that taking oral DHEA-S increases bone mineral density in elderly women with low pre-treatment levels (Joint Bone Spine. 2001. 68. 588-594).
Negative study: In a 2 year RCT in 87 elderly men and 57 elderly women with low DHEA-S, the 29 men on DHEA showed statistically significant, but very little improvement in BMD of the femoral neck, with no significant change in BMD of the lumbar spine or radius; the 27 women showed statistically significant, but very little improvement in BMD of the radius, with no significant change in BMD of the lumbar spine or hip (New Engl J Med. 2006. 355. 1647-1659).
A 12 month RCT in 70 men and 70 women, aged 60-88, randomized to DHEA 50 mg/day or placebo found BMD increases of 1% in the hip for men and women, BMD increase of 2.2% in the lumbar spine in women, with no change in lumbar spine BMD in men (J Clin Endocrinol Metab. 2006. 91. 2986-2993).
In a 2 year RCT in 58 women (aged 65-75), 50 mg/day (in conjunction with 640 IU/day vitamin D and 700 mg/day calcium), mean lumbar BMD increased 1.9% at one year and 3.6% at 2 years in the treatment group; hip BMD did not change. No benefit though in the 55 men aged 65-75, analyzed separately (Am J Clin Nutr. 2009. 89. 1459-1467).
A meta-analysis of 4 RCTs (including a total of 295 women and 290 men over age 55) showed that DHEA supplementation significantly improved the bone mineral density of the lumbar spine, total hip and trochanter in women, but had no significant effect on bone mineral density at any site in men (Clin Endocrinol. 2019. 90. 293-300).
Two additional meta-analysis of randomized controlled trials show that DHEA supplementation increases BMD in women (Gynecol Endocrinol. 2019; 35(11):924-931; Complement Ther Med. 2021; 56:102620).
Adrenalin - high adrenalin levels will cause increased bone turnover.
Cortisol – high cortisol levels will cause increased bone turnover.
Leptin – role in inflammation and bone metabolism; obesity protects against osteoporosis.
Calcitonin – inhibits osteoclasts.
Thyroid hormone
A couple of methodologically flawed studies in the 1980s reported that physiologic doses of thyroid replacement predispose to osteoporosis.
However, a study comparing bone mineral density at several sites in individuals on long term thyroid replacement therapy (average 7.9 years) with bone mineral density of controls matched for multiple variables including age, sex, calcium intake, BMI, smoking status, menopausal status found no evidence of lower bone density in treated patients compared to controls, even though the average replacement dose was 191 mcg/day (Lancet. 1992. 340. 9-13).
The effect of supra-physiological doses of orally administered thyroid hormone (i.e. doses which suppress TSH) on bone density is uncertain; high doses might predispose to osteoporosis.
Vitamins, Minerals and Dietary Supplements for Osteoporosis Prevention/Treatment
Boron
In one study, 3 mg per day of boron was associated with a 44% reduction in calcium loss in the urine (Nutrition Today. Jan/Feb 1988. 4-7).
Multiple possible mechanisms of action.
Reduces urinary losses of calcium and magnesium.
Increases estradiol and testosterone levels.
May enhance conversion of vitamin D to biologically active form.
Food sources of boron include fruits (especially apples, pears, grapes, raisins, dates, and peaches), legumes, and nuts.
Consider a supplemental dose of 1-3 mg a day.
Calcium
Total intake (from diet and supplements) of calcium should be 800-1500 mg calcium/day (with Walter Willett, MD, DrPH asserting that in conjunction with a healthy diet and vitamin D supplementation, 800 mg daily is sufficient - Eat, Drink and Be Healthy. 2001).
The adequacy of intake can be determined by measuring 24 hour urine calcium. It should be greater than 100 mg.
Good dietary sources include green leafy vegetables, canned sardines and salmon.
Calcium supplements
Calcium carbonate (40% calcium by weight) is the cheapest. Absorption is approximately 30% higher if taken with meals. Not absorbed well in those with achlorhydria. This form has been shown in studies to prevent bone loss.
Calcium hydroxyapatite (25% calcium by weight) may be more effective than calcium carbonate in slowing postmenopausal bone loss.
In a 20 month RCT in 40 osteoporotic patients, there was statistically less loss of trabecular bone by quantitative CT in the group which received 1400 mg per day of calcium in the form of calcium hydroxyapatite, compared to the group which received 1400 mg per day of calcium carbonate (Osteoporosis Int. 1995. 5. 30-34).
In a 14 month RCT in 64 postmenopausal women with primary biliary cirrhosis, calcium hydroxyapatite promoted positive cortical bone balance, based on pre- and post-treatment hand radiographs, using the technique of caliper radiogrammetry to assess changes in metacarpal cortical thickness (Am J Clin Nutr. 1982. 36. 426-430
Calcium citrate (22% calcium by weight) may be absorbed more easily; this may be a significant benefit in people over age 60. Absorption is the same whether taken with food or on an empty stomach. Advisable in place of calcium carbonate in patients with pernicious anemia, those taking prescription H2 blockers (Tagamet, Zantac, Pepcid, Axid) or proton pump inhibitors (Prilosec, Protonix, Aciphex, Prevacid, Nexium), and those with constipation or bloating secondary to calcium carbonate. No study data on this form of calcium and prevention of postmenopausal bone loss.
Calcium lactate (13% calcium by weight) may be best absorbed.
Calcium triphosphate (38% calcium by weight) may be a better choice for other forms for postmenopausal women (Mayo Clinic Proc. 2004. 79. 91-97).
Bone meal and dolomite (30% calcium by weight) may contain unsafe levels of lead and other contaminants.
Contrary to folk wisdom, calcium supplementation does not increase the recurrence of calcium oxalate kidney stones. Calcium citrate can actually reduce the risk for stone formation by reducing urinary saturation of calcium oxalate and calcium phosphate.
Although not proven, some experts believe that calcium supplements are more effective if taken at bedtime.
FDA does not monitor bioavailability of calcium supplements. However, bioavailability should be good if the label says "Meets USP Dissolution Standards."
Home measure of bioavailability - place tablet in 30 ml white vinegar at room temperature, stir every 2-3 minutes, expect at least 75% dissolution at 30 minutes.
If you take more than 600 mg of supplemental calcium a day, it will be best absorbed if split into at least two doses.
There is epidemiologic data showing that vegetarians have increased bone density. The potential explanations for the observed association between vegetarianism and increased bone density include:
High concentration of fat in meat interferes with calcium absorption.
High concentration of protein in meat causes increased calcium loss in the urine.
High phosphorus/calcium ratio in meat causes a temporary drop in blood calcium levels which triggers the parathyroid gland to release PTH (a hormone), which in turn causes release of calcium from the bone in order to maintain blood calcium levels. PTH also decreases calcium excretion in the urine - the calcium from the bone ends up deposited in joint spaces and the walls of arteries.
Fiber, and in particular, bran, can inhibit calcium absorption. With time, the body seems able to overcome this inhibition.
Grains - phytic acid in grains may not inhibit calcium absorption because the human intestinal tract can adapt and produce phytase.
Iron supplements can interfere with the absorption of calcium.
NOTE calcium supplementation decreases the absorption of phosphorous, and this may be an issue in those eating a low protein diet (J Am Coll Nutr. 2002. 21. 239-244). This issue can be addressed by using calcium phosphate as a supplemental source of both calcium and phosphorus.
Clinical studies - data is mixed
In a RCT in 36,282 postmenopausal women already enrolled in the WHI, at a mean follow up of 7 years, those randomized to calcium carbonate 1000 mg/day with vitamin D 400 IU/day had a small but statistically significant improvement in hip bone density, but no significant reduction in hip fracture. Note however that women in this study were not necessarily osteoporotic upon enrollment, greater than 50% of these women were on HRT, personal use of calcium and vitamin D was permitted, and when data were excluded for women with less than 80% adherence to therapy, risk of hip fracture was 0.71 (0.52 – 0.97). Risk of renal calculi was increased by 17% (New Engl J Med. 2006. 354. 669-683 and 750-752).
There were 12% fewer hip fractures in the treatment group, using an intent-to-treat analysis, but this was not statistically significant.
The mean intake of calcium from diet and supplements at baseline was 1150 mg per day! In the subgroup of subjects with low or moderate calcium intake at baseline, there was a 22% reduction in hip fracture, using an intent-to-treat analysis.
In the subgroup of women compliant with taking the calcium and vitamin D, there were 29% fewer fractures.
A meta-analysis of 15 RCTs including 1806 patients followed for at least a year showed that calcium supplementation alone has a small positive effect on bone density. There was a trend toward reduction in vertebral fractures, but no data regarding an effect on the incidence of nonvertebral fractures (Endocrin Rev. 2002. 23. 552-559).
In a two year trial in 59 postmenopausal women divided into 4 groups, those who received placebo had a decrease in bone density of the lumbar spine (-3.53%), those who received calcium citrate-malate 1000 mg a day also had a decrease in bone density (-1.25%), those who received trace minerals daily (copper 2.5 mg, manganese 5 mg, and zinc 15 mg) had a decrease in bone density (-1.89%), BUT those who received calcium and trace minerals had an increase in bone density (+1.48%) [J Nutr. 1994. 124. 1060-1064].
Benefit seen in a trial using tricalcium phosphate (New Engl J Med. 1992. 327. 1637-1642).
In a 2 year RCT in 301 healthy postmenopausal women, (1) in the subgroup with less than 400 mg of dietary calcium intake/day at baseline, calcium citrate malate 500 mg daily prevented bone loss at the hip, spine, and radius, and calcium carbonate 500 mg daily prevented bone loss at the hip and radius, but not the spine, whereas (2) in the subgroup of women with calcium intake of 400-650 mg/day, there were no differences between the placebo group, calcium carbonate group, and calcium citrate malate group, with all 3 groups maintaining bone density at the hip and radius, but losing bone density at the spine (N Engl J Med. 1990. 323. 878-883).
A systematic review and meta-analysis of 15 RCTs (n=1533) of dietary calcium intake concluded that dietary calcium increased bone mineral density by 0.6% to 1% at the total hip and total body at 1 year, and by 0.7% to 1.8% at the lumbar spine, femoral neck, total hip and total body at 2years. This same study examined calcium supplementation as monotherapy in 51 RCTs (n=12,257) and concluded that supplementation increased bone mineral density by 0.7% to 1.8% (BMJ. 2015. 351. h4183 and ACP Journal Club. 2015. 164. JC5).
A systematic review of 20 trials of calcium supplementation and risk of fracture in persons > 50 years of age showed an 11% reduction in relative risk (NNT of 77), but a meta-analysis of the 4 studies (out of the total or 20 studies) with a low risk for bias showed no effect of calcium supplementation on fracture risk (BMJ. 2015. 351. h4580 and ACP Journal Club. 2015. 164. JC4).
A meta-analysis of 33 RCTs (n = 51,145) in community-dwelling adults older than age 50 found that use of supplements that included calcium, vitamin D, or both was not associated with a significant difference in the risk of hip fracture, as compared with placebo or no treatment (JAMA. 2017. 318. 2466-2482).
NOTE that epidemiologic and cross cultural data shows a POSITIVE correlation between increased consumption of milk and dairy products and hip fractures - see the data on the “Nutrition” page of this web site and scroll down to the section on “Milk.”
Consider a supplemental dose of 300-500 mg daily
Copper
Copper is essential for the formation of the collagen component in bone.
Benefit of small doses is based on test tube studies, animal studies, a two year clinical trial in 73 women who received either 3 mg/day of copper amino acid chelate or placebo (Proc NutrSoc. 1995. 54. 191A), and a second 2 year trial at a dose of 3 mg/day (J Trace Elem Exp Med. 1996. 9. 87-94).
Foods rich in copper include eggs, green leafy vegetables, legumes, nuts, organ meats, poultry, and whole grains.
Consider a supplemental dose of 2-3 mg a day; BEWARE that excess ingestion of copper is associated with health risks.
Creatine (in conjunction with resistance training)
In a 12 month RCT of 47 postmenopausal women who underwent resistance training 3 times per week, those who received creatine 0.1 gram per kg of body weight per day showed a lower mean loss of BMD of the femoral neck, and significantly increased femoral shaft periosteal width, a predictor of bone bending strength (Med Sci Sports Exerc. 2015. 47. 1587-1595).
Cyplexinol®
This is a unique complex of osteoinductive proteins known as Bone Morphogenetic Proteins (BMPs) – proteins which exhibit capability for joint-tissue repair, and which have intrinsic anti-inflammatory properties. These proteins naturally stimulate bone and cartilage growth (presumably via stem cell activation) at the same time that they down-regulate inflammatory cytokines.
Osteoinductivity is defined as the ability of a protein complex to activate, stimulate, and differentiate mesenchymal stem cells into osteoblasts and chondrocytes, which in turn produce bone and cartilage tissue.
Bone Morphogenetic Proteins (BMPs) have been used by orthopedic surgeons since the 1980’s, within surgical devices and attached to the bone. Thousands of published studies supporting safety and efficacy.
Derived from grass-fed, closed-herd cows raised on lands that are certified pesticide-free for at least 3 years.
In a case control study of a 59 year old female, nonsmoker, there was a statistically significant 51.5% increase in bone mineral density (by DEXA) after 34 month s of Cyplexinol administration (IMCJ. 2013. 12[5]. 45-48).
Usual dosage is 150 mg daily
DHEA - see section on hormones above in this outline
Dihuang Decoction (DHD)
This is a TCM remedy, consisting of six herbs, including Rhemannia glutinosa, and Wolfiporia cocos
Dose is one twice a day on two days of the week
In a one year study of 72 patients, comparing this herb with alendronate 70 mg weekly (both groups also took 600 mg calcium carbonate and 0.5 mcg calcitriol), lumbar and femoral neck bone density were statistically significantly improved to a similar degree. Furthermore, beta-CTX, a marker of bone turnover decreased to a similar degree in both groups. Finally serum osteoclast (SOST) levels remained comparable in both treatment groups (China J Ortho Traum. 2019. 32. 535-538).
Fish oil - negative trial
In a RCT of 2157 adults aged 70 years or older, fish oil at a dose of 330 mg EPA + 660 mg DHA per day did not affect the incidence of nonvertebral fractures at 3 years of follow-up (JAMA. 2020. 324. 1855-1868).
Folate
Postmenopausal women have a reduced capacity to metabolize homocysteine, as demonstrated by a study using a methionine load test in premenopausal and postmenopausal women.
High homocysteine levels are correlated with an increased risk of osteoporosis.
Supplemental folate lowers homocysteine levels.
Grains in the U.S. are now fortified with folate, so folate deficiency is much less common than in the early 1990’s.
In a study in which the trabecular heads were examined in 94 men and women who underwent elective hip arthroplasty, histomorphometric analysis showed significantly lower trabecular thickness and trabecular area in those patients with serum folate below the median, as compared with those with serum folate above the median, even though BMD was similar in both groups (Am J Clin Nutr. 2009. 90. 1440-1445).
The 0.4 mg of folate in a multivitamin should provide adequate supplementation for most women.
Folate 5 mg/day along with Vitamin B12 1500 mcg/day markedly reduced the risk of hip fractures in a two year trial in 628 Japanese patients, mean age 71 years, with residual hemiplegia from a stroke. The number of falls per person did not differ between the groups. In this study, treatment of 15 people with this regimen of vitamin B12 and folate would prevent one hip fracture! (JAMA. 2005. 293. 1082-1088).
Consider a supplemental dose of 1-5 mg a day if homocysteine is high, and if homocysteine does not decrease, consider 5-MTHF 400 mcg a day.
Genistein
This is an isoflavone phytoestrogen which is abundant in soybean products, and which structurally resembles 17 beta estradiol (Endocrinology. 1998. 139. 4252-4263).
Genistein has greater affinity for the estrogen beta receptor in bone than the estrogen alpha receptor in reproductive tissue, and thus is a natural SERM.
Genistein 54 mg/day increased BMD at the lumbar spine and femoral neck in a short RCT in 90 patients (J Bone Miner Res. 2002. 17. 1904-1912).
A 24 month RCT in 389 postmenopausal women with osteoporosis showed that genistein 54 mg/day had positive effects on BMD. Note though that 19% in the genistein group versus 8% in the placebo group discontinued treatment due to side effects, most often GI side effects with genistein (Ann Intern Med. 2007. 146. 839-847).
Ipriflavone
This is a derivative of a naturally occurring class of isoflavones found mainly in soy.
Approved for treatment of osteoporosis in some European and Asian countries.
Metabolites may have direct estrogenic effects, and ipriflavone thus may potentiate the effect of estrogen.
Clinical trial data to date is conflicting:
Benefit seen in a 1 year RCT in 105 postmenopausal women who received 600 mg/day (Gynecol Endocrinol. 1997. 11. 289-293).
Benefit seen in a 2 year RCT in 255 postmenopausal women who received 200 mg three times a day (Osteoporosis Int. 1997. 7. 119-125).
Benefit seen in a study with 57 women (mean age 51 years) with osteopenia or osteoporosis randomized to receive ipriflavone 600 mg/day or calcium lactate 800 mg/day for one year. Lumbar bone mineral density fell 0.8% in the ipriflavone group versus 3.1% in the calcium group (Horm Res. 1999. 51. 178-183).
However, in multicenter 4 year study of 474 postmenopausal white women in which 234 received ipriflavone 200 mg 3 times a day and 240 received placebo (all women received 500 mg/day of calcium), ipriflavone did not prevent bone loss or affect biochemical markers of bone metabolism (JAMA. 2001. 285. 1482-1488).
Ipriflavone Multicentre European Fracture Study is an ongoing 3 year RCT of 460 non-obese postmenopausal women with low bone density, with vertebral non-traumatic fractures as the primary endpoint, and changes in bone density as the secondary endpoint.
Adverse effects
May produce a slowly progressive lymphocytopenia (in 13% of participants in one study).
Interactions with theophylline and coumadin have been noted.
Dose in most in published studies is 200 mg three times a day.
Maca
Red maca shown to reverse experimentally induced osteoporosis (Gonzalez GF et al. Rev Peru Med Exp Salud Publ. 2014)
Magnesium
The typical American diet contains only 250 mg of magnesium per day, less than the RDA of 350 mg, and far less than the optimal intake of approximately 600 mg.
Approximately 60% of magnesium in the body is found in bone - most of the magnesium in bone is in cortical bone, as an integral part of the apatite crystal.
Magnesium is a cofactor for enzymes which regulate calcium metabolism.
Stress (physical, chemical, emotional) depletes magnesium.
Magnesium deficiency is associated with abnormal calcification of bone, based on data from a magnesium load test in combination with infrared spectroscopy.
Magnesium is hypothesized to strengthen bone independent of BMD
Clinical trial data is limited
A trial in postmenopausal women, using doses of 250 – 750 mg of magnesium daily for 6 months, followed by 250 mg/day for 6-18 months, was associated with an increase in BMD in 71% of the women, even though not accompanied by calcium supplementation (Magnes Res. 1993. 6. 155-163).
A two year trial in 31 postmenopausal women showed an increase in BMD at the end of one year in 22 of the 31 women; only 10 women completed the entire two year trial (Nutr Rev. 1995. 53. 71-7
Short term oral magnesium supplementation slowed bone turnover in postmenopausal osteoporotic women (Biol Trace Elem Res. 2010. 133. 136-143).
Beware that too much supplemental magnesium can cause a fast transit time which can manifest as diarrhea and also cause malabsorption of other nutrients.
BEWARE of excess magnesium intake in chronic kidney disease (CKD).
Consider a supplemental dose of 300-600 mg a day.
Manganese
Stimulates production of mucopolysaccharides, which provide a structure upon which calcification can take place.
EDTA, a common preservative in food, may interfere with absorption of manganese.
Food sources of manganese include beans, cereals, oatmeal, nuts, pineapple, spinach, tea, and whole wheat.
Consider a supplemental dose of 5-20 mg a day.
Melatonin
3 mg at bedtime for one year increased BMD by 2.3% at the femoral neck (p < 0.01) and 3.6% at the lumbar spine (p=0.04) in a placebo-controlled RCT of 81 postmenopausal women with osteopenia. In this same trial, 1 mg at bedtime was ineffective. Mechanism of action is unknown (J Pineal Res. 2015. 59. 221-229).
Phosphorous
Principle anion in bone mineral; the inorganic hydroxyapatite in bone is composed primarily of calcium and phosphorous.
Most of the population obtains adequate (or too much) phosphorous from the diet (phosphorous is plentiful in protein), BUT it is estimated that 10% of women over age 60 and 15% of women over age 80 have a phosphorous intake less than 2/3 of the RDA.
Calcium carbonate and calcium citrate supplements will bind dietary phosphorous and thus inhibit absorption. A calcium triphosphate or calcium hydroxyapatite supplement avoids this potential problem.
Excess phosphorous intake is associated with excess mortality, based on data in 9686 healthy adults in NHANES III (1988-1994). Dietary phosphorous intake was assessed using a 24 hour dietary recall (Am J Clin Nutr. 2014. 99. 320-327).
Potassium
Potassium helps regulate calcium absorption.
High dietary potassium intake is correlated with higher bone density.
BEWARE of high potassium intake if chronic kidney disease is present.
Resveratrol
In a 16 week RCT of 74 middle aged obese men with metabolic syndrome, bone mineral density of the lumbar spine increased in those who received resveratrol 1000 mg daily (Ornstrup MJ et al. J Clin Endocrinol Metab. Epub 10/16/14).
Silicon
Important in small amounts for bone health via regulation of bone mineralization and stimulation of type I collagen synthesis (Bone. 2003. 32. 127-135).
Recently recognized as an essential nutrient; unknown whether typical diet includes an adequate amount.
The most common substance on earth after oxygen.
Food sources include rice bran and brown rice.
Consider supplemental dose of 1-10 mg a day; consider supplementing in the form of orthosilicic acid as silicon must be solubilized into orthosilicic acid in the stomach as a prerequisite to absorption.
Soy protein (see also ‘genistein’ and ‘ipriflavone’ above)
In one study, a diet containing 40 grams/day of isolated soy protein significantly increased bone mineral density in the spine when compared to a control group ingesting a non soy protein diet (J Clin Endocrinol Metab. 1998. 83. 2223-2235). No benefit on hip bone mineral density was observed.
A 24 week study in 48 postmenopausal women showed that the group randomized to receive 40 gm/day of isoflavone-rich soy protein isolate showed an increase in BMD, whereas the whey protein control group showed a loss of BMD (Am J Clin Nutr. 2000. 72. 844-852).
A two year, 4 arm randomized study in 89 postmenopausal women showed that those who received 500 ml/day of soymilk, containing 76 mg/day of isoflavones showed an increase in spinal BMD, whereas the placebo group had a loss of BMD (Eur J Nutr. 2004. 43. 246-257).
A negative study was a RCT with 202 healthy postmenopausal women aged 60-75 who received either 25.6 grams of soy protein containing 99 mg isoflavones or total milk protein as placebo. At 1 year, even though the serum genistein levels were much higher in the treatment group (615 versus 17 nmol/L), there was no difference in bone mineral density, cognitive function, or plasma lipids (JAMA. 2004. 292. 65-74).
In a cohort study of 24, 403 postmenopausal women followed for 4.5 years, there was a significant reduction in risk of fracture in women within 10 years of menopause (Arch Intern Med. 2005. 165. 1890-1895).
A 9 month RCT in 61 postmenopausal women receiving soy protein isolate showed statistically significant decreases in biomarkers of bone turnover, but no change in bone mineral density (Menopause. 2007. 14. 481-488).
A meta-analysis of 10 RCTs (n=608) found that soy isoflavone intake for 6 months attenuates bone loss in the spine of postmenopausal women, with greatest benefit seen in those consuming more than 90 mg per day of isoflavones (Clin Nutr. 2008. 27. 57-64). However, two other meta-analyses concluded that soy isoflavones do not prevent bone loss (Bone. 2009. 44. 948-953; J Womens Health. 2010. 19. 1609-1617).
Another negative study was a 1 year RCT of soy food or isoflavone supplementation versus placebo in 131 ambulatory women > age 60 (Am J Clin Nutr. 2009. 90. 234-242).
A 3 year RCT of soy isoflavone supplementation in 234 postmenopausal women showed a significant increase in bone mineral density in the femoral neck for the intervention group receiving 120 mg/day of isoflavone supplementation (Am J Clin Nutr. 2010. 91. 218-230).
The SPARE study, a NIH-funded 2 year RCT of 248 women aged 45-60 and within 5 years of menopause found that 200 mg/day of soy isoflavones did NOT affect bone loss in the lumbar spine, total hip, or femoral neck (Arch Intern Med. 2011. 171. 1363-1369 and Invited Commentary 1369-1370).
A literature review suggests that soy supplementation does not offer protection against osteoporosis (Altern Ther Health Med. 2014. 20[suppl 1]. 39-51).
Strontium
A Mayo Clinic trial in which 32 patients received strontium lactate for up to 3 years reported probable improvement in bone density, less bone pain, and no significant side effects (Proc Staff Meetings Mayo Clinic. 1959. 34. 329-334).
A 2 year RCT in 353 osteoporotic women (STRATOS Study) in which strontium was administered in doses of 170 mg, 340 mg, and 680 mg showed increases bone density in a dose dependent manner. Those receiving 680 mg per day showed positive changes in markers of bone metabolism and fewer new vertebral fractures (J Clin Endocrinol Metab. 2002. 87. 2060-2066).
A 3 year RCT in 1649 postmenopausal women with at least one previous vertebral compression fracture who received either 2 grams of strontium ranelate powder (providing 680 mg/day of strontium) or placebo showed an increase in bone density and a reduction in symptomatic vertebral fractures in the treatment group. Adverse effects were uncommon. Treatment of 17 postmenopausal women who with a history of vertebral compression fractures for 3 years will prevent one new symptomatic vertebral compression fracture (Osteoporosis Int. 2002. 13. 521; New Engl J Med. 2004. 350. 459-468).
A 3 year trial in over 7000 postmenopausal women with osteoporosis showed that strontium ranelate 2 grams/day decreased fracture risk and increased bone density (Bone. 2006. 38. 19-22).
A 5 year trial in 5091 postmenopausal women, using strontium ranelate 2 grams/day (TROPOS study) showed that the incidence of nonvertebral fractures in the treatment group was 15% lower than in the placebo group (p=0.032) and the incidence of vertebral fractures in the treatment group was 24% lower than in the placebo group (p<0.001). In this study, the magnitude of reduction in fracture incidence relative to placebo diminished with time (Arthritis Rheum. 2008. 58. 1687-1695).
A 5 year extension of the TROPOS study in which women were invited to continue treatment in an open-label fashion for an additional 5 years – 239 women completed the 5 year extension trial, during which time they received 680 mg/day elemental strontium, 1000 mg/day calcium, and 400-800 IU/day vitamin D. Over 10 years, lumbar BMD increased continuously and significantly (p<0.01 versus the previous year, with a 34.5% mean increase from baseline at year 10, and a 7.9% mean increase from year 6 to year 10. The incidence of new fractures in years 6-10 was significantly lower in the treatment group (Osteoporosis Int. 2012. 23. 1115-1122). In a Commentary (Townsend Letter. 12/12. Pg 38)., Dr Alan Gaby states that the data showed that the fracture-preventing effect of strontium tended to wane in years 6-10 despite progressive increases in BMD, and this suggests that some of the new bone formed during long term strontium treatment is not of high quality.
Mechanism of action (as per Alan Gaby Commentary in Townsend Letter. 12/14 Pg 33).
Low dose – a few strontium atoms replace calcium in hydroxyapatite crystals, and appear to enhance bone quality and strength.
High dose - pharmacological doses of strontium are thought to be mediated by adsorption of strontium onto the crystal surface (as opposed to incorporation into the crystal lattice), where the strontium promotes bone formation and inhibits bone resorption. There is some concern that long term high dose strontium in humans might cause mineralization defects, and thus in clinical practice it may be wisest to consider a dosage reduction after one year, or to treat with high doses for one year on and one year off.
Risks: as additional data has been gathered for strontium ranelate, the probability of risk may exceed the possibility of benefit
European Medicines Agency released a warning about the use of strontium ranelate - the relative risk of serious heart problems is 1.6 as compared with placebo, and strontium ranelate is associated with an increased risk of venous thromboembolism. The number of fractures prevented by strontium was similar to the number of extra cases of pulmonary embolism, thromboembolism and myocardial infarction, based on review of seven trials and five publicly available regulatory documents (BMJ Open. 2014. 2014. e005787).
Strontium (high dose) is considered contra-indicated in those with cardiovascular disease and uncontrolled hypertension (Osteoporosis Int. 2014. 25. 397-398).
At least 47 reports of drug hypersensitivity (DRESS syndrome) [Osteoporosis Int. 2013. 24. 1751-1757].
In August 2017, the manufacturer of strontium ranelate, which is licensed as a drug in Europe, withdrew this compound from the market world-wide (BMJ. 2017. 357, j2580).
Strontium citrate in high doses is readily available in the US; it is unknown if the risk of strontium citrate are similar to those with strontium ranelate.
Note that because strontium accumulates in bone and attenuates X-rays more than calcium (strontium has a higher atomic mass), DEXA studies will overestimate BMD when patients are taking high dose strontium. Alert the radiologist reading the DEXA scan.
Consider a daily supplemental dose of 2-6 mg/day for prevention.
Vitamin A
·BEWARE excess dietary intake of Vitamin A is associated with decreased bone mineral density and an increased risk of hip fractures in some but not all studies. The presumed mechanism is that high intake of vitamin A antagonizes vitamin D - these vitamins likely compete for absorption, and there is evidence that vitamin A inhibits vitamin D activated gene expression. Go to web outline on ‘Vitamins and Minerals’ for details of the published studies.
A nested case-control study of the incidence of hip fracture showed that the relative risk of hip fracture was 2.1 for persons with vitamin A intake greater than 1500 mcg (5000 IU) per day (Ann Intern Med. 1998. 129. 770-778).
In the Nurses' Health Study, relative risk of hip fracture was 1.64 in women with vitamin A intake greater than 1500 mcg per day, compared with those whose intake was less than 500 mcg per day (JAMA. 2002. 287. 47-54).
A prospective 30 year population-based longitudinal study in 2232 men showed an inverse relationship between serum retinol levels and hip fracture, with a relative risk of hip fracture of 2.47 in men in the highest quintile of serum retinol, as compared with the middle quintile (N Engl J Med. 2003. 348. 287-294 and 347-349).
HOWEVER, in a study of men aged 18-58 who took 25,000 IU vitamin A daily for 6 weeks, there was not an increase in bone turnover (J Nutr. 2002. 132. 1169-1172).
AVOID intake of more than 10,000 IU per day total, avoid intake of more than 3000 IU per day in vitamins/supplements (preformed vitamin A).
Vitamin B6 (pyridoxine)
Supplementation reduces homocysteine levels and increases progesterone levels.
Widespread industrial use of vitamin B6 antagonists (hydrazines and hydrazides) may mean that consumption of RDA of this vitamin is inadequate for many individuals.
A small study showed low P5’P (active form of vitamin B6) levels in 10 of 20 patients admitted for nontraumatic hip fracture but only 3 of 21 patients admitted for elective arthroplasty (ActaOrthop Scand. 1992. 63. 635-638).
In a study in which the trabecular heads were examined in 94 men and women who underwent elective hip arthroplasty, histomorphometric analysis showed significantly lower trabecular number (defined as the number of trabeculae per unit of length) in those patients with serum B6 below the median, as compared with those with serum B6 above the median, even though BMD was similar in both groups (Am J Clin Nutr. 2009. 90. 1440-1445).
Consider a supplemental dose of 10-50 mg a day.
Vitamin B12
Supplementation may reduce homocysteine levels.
NOTE many seniors do not absorb this vitamin well from food sources as vitamin B12 in food is bound to protein; B12 deficiency or insufficiency is common in seniors.
Recent population-based studies suggest that correlation of B12 status and bone mineral density (J Nutr. 2003. 133. 801-807; J Bone Miner Res. 2005. 20. 152-158).
Vitamin B12 affects osteoblast activity and bone formation. It increases osteocalcin concentration (osteocalcin is a major protein in bone, and it binds with calcium) and promotes collagen cross linking (N Engl J Med. 1988. 319. 70-75; Metabolism. 1996. 45. 1443-1446; JAMA. 2005. 293. 1082-1088).
Vitamin B12 1500 mcg/day along with folate 5 mg/day markedly reduced the risk of hip fractures in a two year trial in 628 Japanese patients, mean age 71 years, with residual hemiplegia from a stroke. The number of falls per person did not differ between the groups. In this study, treatment of 15 people with this regimen of vitamin B12 and folate would prevent one hip fracture! (JAMA. 2005. 293. 1082-1088).
Consider a supplemental dose of 500 – 1500 mcg a day.
Vitamin C
Important in small amounts for bone health; promotes formation of collagen, which is the bone connective tissue.
In the Framingham Osteoporosis Study in 958 men and women, at 15-17 years of follow up, those in the highest third of vitamin C intake (median 305 mg/day) had a 44% lower risk of hip fracture than those in the lowest third of vitamin C intake (median 97 mg/day). When hip fracture was looked at as a function of dietary vitamin C intake versus supplemental vitamin C intake, supplements accounted for 28% of vitamin C intake in the cohort, and it was specifically supplemental vitamin C intake which was correlated with a lower risk of hip fracture, with no effect of dietary vitamin C intake on hip fracture risk. This epidemiologic data does not necessarily mean cause and effect; the benefit might be due to confounding effects, such that those taking vitamin C supplements are healthier than those not taking supplements (Data presented at 2008 annual meeting for Bone and Mineral Research).
Consider a supplemental dose of 100-200 mg a day.
Vitamin D
Dose of vitamin D for prevention of bone loss
RCTs show that vitamin D 800 IU is more effective than vitamin D 400 IU at stabilizing bone density (measured by DEXA scan).
2000 IU daily for two years ineffective at increasing bone mineral density in a subcohort of 771 participants in the VITAL study. 25 OH vitamin D level was 27.6 ng/ml at baseline; changes in bone mineral density in this subcohort did NOT vary according to baseline vitamin D level (J Bone Miner Res. 2020. 35. 883-893).
High dose vitamin D increases bone loss based on a RCT of 333 adults in Calgary with a baseline 25 hydroxy vitamin D level in the normal range, randomized to 400 IU, 4,000 IU or 10,000 IU daily. Treatment with 4,000 IU daily and 10,000 IU daily significantly decreased BMD of the lower radius, as compared with 400 IU daily, and 10,000 ID daily significantly decreased BMD of the tibia, as compared with 400 IU daily (JAMA. 2019. 322. 736-745).
The data on reduction in fracture risk with vitamin D is mixed with the preponderance of data showing no benefit of vitamin D supplementation
A meta-analysis of 5 RCTs using hip fracture (9294 participants) as an endpoint and 7 RCTs using nonvertebral fractures as an endpoint (9820 participants) found that if studies were pooled based on the administration of low dose (400 IU daily) or higher dose (700-800 IU daily) of vitamin D, oral vitamin D 700-800 IU daily appears to reduce the risk of hip fracture (by 26%) and any nonvertebral fractures (by 23%) in ambulatory or institutionalized older individuals. Vitamin D 400 IU daily is not sufficient for fracture prevention (JAMA. 2005. 293. 2257-2264). Many of the patients in the studies in this meta-analysis were nursing home residents, and this may explain in part the positive findings (ACP Journal Club. 2005. 143. 72).
HOWEVER a Cochrane analysis of 18,668 individuals in 7 trials failed to show a significant reduction in fracture risk with vitamin D alone (Cochrane Database Syst Rev. 2005. CD000227). This same Cochrane analysis did find a 19% reduction in hip fracture with a combination of calcium and vitamin D, but the benefit seemed to be restricted to persons living in institutionalized settings (ACP Journal Club. 2006. 144. 14).
A study of 2686 adults 65 to 85 years of age showed that those who took vitamin D3 as a 100,000 IU capsule every 4 months for 5 years had a statistically reduced risk of fracture (8.8% versus 11.1%; number needed to treat = 44). Subgroup analysis showed that the benefit was restricted to women. The daily supplemental dose can be calculated at 100,000 IU divided by 122 days = 820 IU/day (BMJ. 2003. 326. 469-472).
HOWEVER, a large methodologically rigorous 5 year study in 5292 patients with a previous fracture (RECORD) found no difference in rates of repeat fractures in those who took vitamin D 800 IU per day (Lancet. 2005. 365. 1621-1628). Negative result may have been a function of poor compliance (54.5% at two years) or an underpowered study (ACP Journal Club. 2005. 143. 74). Mean 25 OH vitamin D levels increased from 15.2 to 24.8; a level of >30 ng/mL is required for antifracture efficacy (Alt Med Alert. 2009. 12. 37-43).
Another NEGATIVE trial included 3454 community-dwelling women over age 70 and with one or more risk factors for hip fracture. At a median follow up of 25 months, those who took calcium 500 mg twice a day with vitamin D 400 IU twice a day did not have a reduced fracture risk (BMJ. 2005. 330. 1003-1006). This study may have been underpowered to detect a reduction in fracture risk, and the poor compliance, 56.6% may also have contributed to the negative result (ACP Journal Club. 2005. 143. 73).
Despite these negative trials, a meta-analysis of 12 RCTs for nonvertebral fracture (42,297) and 8 RCTs for hip fracture (n= 40,886) comparing vitamin D with or without calcium to calcium or placebo found that when trials were pooled based on the dose of supplemental vitamin D, benefit was seen in the trials using a supplemental dose of vitamin D > 400 IU/day. When a higher dose of vitamin D was administered, the RR of nonvertebral fracture was 0.80 (0.72-0.89; n+33,265 from 9 trials) and the RR of hip fracture was 0.82 (0.69-0.97; n=31,872 from 5 trials). When stratified by institutional status, the reduction in nonvertebral fractures in community dwelling individuals receiving higher dose vitamin D was ~29% and the reduction in institutionalized older individuals receiving higher dose vitamin D was ~15%. The benefit was independent of whether or not supplemental calcium was administered with the supplemental vitamin D (Arch Intern Med. 2009. 169. 551-561).
NEGATIVE TRIAL – a RCT in 2256 community dwelling women (median baseline 25 OH vitamin D 49 nmol/L – 20 ng/ml) surprisingly showed that those supplemented once a year each fall for 3-5 years with 500,000 IU of cholecalciferol had an increased risk of fractures (and falls), despite normalization of 25 OH vitamin D levels. The explanation for this surprising result is uncertain (JAMA. 2010. 303. 1815-1822 and editorial).
NEGATIVE TRIAL for high dose - in a 1 year RCT of 297 women with a mean baseline serum 25 OH Vitamin D level of 28.4 ng/ml, mean bone mineral density was similar in those randomized to 6500 IU daily, as compared with those randomized to 800 IU daily (Osteoporosis Int. 2012. 23. 201-211).
An updated Cochrane analysis of 91,791 individuals in 50 RCTs and 3 quasi-RCTs failed to show a significant reduction in fracture risk with vitamin D supplementation alone in postmenopausal women and older men. In fact vitamin D supplementation was associated with a non-significant 12% increased risk of hip fractures and a non-significant 3% increased risk of all fractures. However, in the 10 trials (n = 49,976) which examined vitamin D plus calcium supplementation, there was a 16% decreased risk of of hip fracture and a 5% decreased risk of all fractures, with both of these decreases of borderline clinical significance (Cochrane Database Syst Rev. 2014. CD000227).
NEGATIVE TRIAL with high dose once-a-month administration of vitamin D: In the Vitamin D Assessment study, in which 5110 New Zealand adults were randomized to placebo or an initial dose of 200,000 IU vitamin D, followed by 100,000 IU once a month, after a median treatment of 3.4 years, the proportion of participants who experienced a non-vertebral fracture was non-significantly higher in the high dose vitamin D group [6% vs. 5%, p=0.15] (Lancet Diabetes Endocrinol. 2017. 5. 438-447).
NEGATIVE REVIEW: a systematic review and meta-analysis of 81 RCTs (n = 55,537) of the effect of vitamin D supplementation on the incidence of fractures (42 trials), falls (37 trials) and bone mineral density (41 trials). The authors report that vitamin D supplementation in pooled analyses had no significant effect on total fracture, hip fractures, falls or bone mineral density (Lancet Diabetes Endocrinol. 2018. 6. 847-858).
NEGATIVE REVIEW: a systematic review and meta-analysis of 16 large RCTs (> 500 participants in each trial) of vitamin D alone (n = 34,243) reported that vitamin D alone (median equivalent daily dose of 833 IU/day) did not reduce fracture risk. In the 6 large RCTs which evaluated vitamin D with calcium (n = 49,282) there was a small (6%) reduction in overall fracture risk (JAMA Netw Open. 2019. 2. e1917789). Of note for comparison, a systematic review and meta-analysis of bisphosphonates showed a 47% reduction in fracture risk (Osteorosis Int. 2017. 28. 3289-3300).
NEGATIVE RCT: In an ancillary study to the VITAL study of 25,871 participants, supplemental vitamin D3 2000 IU daily did not have an effect on total fractures at a median follow-up of 5.3 years (N Engl J Med. 2022. 387. 299-309 and editorial 368-370).
Vitamin D may prevent falls - clinical data is mixed with the preponderance of data showing no benefit of vitamin D supplementation
A meta-analysis of 5 randomized, controlled trials involving 1237 participants found that vitamin D supplementation (400-800 IU) in seniors over age 60 reduces the risk of falling by 22%. The number needed to treat to prevent one fall is only 15. The presumed mechanism is through muscle strength benefits (JAMA. 2004. 291. 1999-2006).
A 3 year RCT in 199 men and 246 women over age 65 and living at home found that cholecalciferol 700 IU/day with calcium citrate malate 500 mg/day reduced the risk of falls by 46% in women and 65% in the subgroup of less active women, but had no significant impact on falls in men (Arch Intern Med. 2006. 166. 424-430).
A meta-analysis of 8 RCTs of supplemental vitamin D showed that doses of 700-1000 IU/day prevented falls, but doses < 700 IU/day did not (Bischoff-Ferrari HA. BMJ. 2009. 339. b3692).
Negative trial – a RCT in 2256 community dwelling women (median baseline 25 OH vitamin D 49 nmol/L – 20 ng/ml) surprisingly showed that those supplemented once a year each fall season for 3-5 years with 500,000 IU or cholecalciferol had an increased risk of falls (and fractures), despite normalization of 25 OH vitamin D levels. The explanation for this surprising result is uncertain (JAMA. 2010. 303. 1815-1822 and editorial).
A systematic review reported that vitamin D was associated with a reduced risk of falls, but the quality of the evidence was low to moderate (J Clin Endocrinol Metab. 2011. 96. 2997-3006).
However, a meta-analysis of 20 RCTs (n = 29,535) did not show benefit (Lancet Diabetes Endocrinol. 2014. 2. 573-580).
In a RCT of 107 long term care residents over age 60, high dose vitamin D, 100,000 IU once a month was associated with a significantly lower risk of respiratory infection (RR = 0.67), BUT falls were twice as common in the group supplemented with vitamin D (p < 0.001) [Ginde AA et al. J Am Geriatr Soc. ePub 11/16/16].
NEGATIVE REVIEW: a systematic review and meta-analysis of 81 RCTs (n = 55,537) of the effect of vitamin D supplementation on the incidence of fractures (42 trials), falls (37 trials) and bone mineral density (41 trials). The authors report that vitamin D supplementation in pooled analyses had no significant effect on total fracture, hip fractures, falls or bone mineral density (Lancet Diabetes Endocrinol. 2018. 6. 847-858).
NEGATIVE STUDY: In the STURDY trial, a response-adaptive RCT of 688 participants aged 70 years or older, with elevated fall risk and low serum 25 OH vitamin D levels; randomized to 200 IU daily vitamin D3 (control group), 1000 IU daily vitamin D3, 2000 IU daily vitamin D3 and 4000 IU daily vitamin D3 found no benefit of vitamin D at any dosage for reducing falls. This trial was funded by the National Institute of Aging, and was solicited to be done with this design based on conflicting data from prior studies (Ann Intern Med. 2021. 174. 145-156).
Vitamin D may increase muscle strength
6 months of vitamin D supplementation led to significant improvements in isometric knee extensor strength (Aging. 2000. 12. 455-460).
In a RCT of 56 elderly institutionalized Brazilians, mean age 78, those randomized to receive 6 months of vitamin D3 of vitamin D supplementation (150,000 IU once a month for 2 months, followed by 90,000 IU/month for 4 months) showed a 16.4% increase in strength of hip flexors (p=0.0001) and a 24.6% increase in the strength of the knee extensors (p=0.0007). Muscle strength did not improve in the placebo group. Median 25 hydroxy vitamin D level at baseline was 18 ng/dl (Ann Nutr Metab. 2009. 54. 291-300).
Low 25-OH-vitamin D levels are correlated with sarcopenia (J Clin Endocrinol Metab. 2003. 88. 5766-5772).
In a 6 month, 2 x 2 RCT in 113 elderly institutionalized females (average age 80), dynamic muscle strength (and hip BMD) increased in the group receiving 1600 IU per day vitamin D3 as well as the group receiving 880 IU per day vitamin D3. Note that in this trial (1) 57% of participants had a baseline 25 hydroxy vitamin D level less than 20 ng/ml, (2) even though the 25 hydroxy vitamin D level increased to a significantly greater extent in the 1600 IU per day supplement group, dynamic muscle strength and BMD increases in the low dose and high dose vitamin D3 groups were similar, (3) isometric strength and muscle mass did not change in any of the groups, and (4) whole body vibration training had no effect on BMD, muscle strength or muscle mass (J Bone Miner Res. 2011. 26. 42-49).
A review of 12 RCTs in adults > 60 years of age (n=2146) found that vitamin D3 at doses of 800 – 1000 IU daily may improve muscle strength and balance among older adults, but supplementation is not associated with improvement in gait. At doses < 800 IU per day, there is no effect on balance or muscle strength (J Am Geriatr Soc. 2011. 59. 2291-2300).
Vitamin D is necessary for the active intestinal absorption of calcium and phosphorus.
BEWARE Vitamin D is a fat soluble vitamin, and too much (more than 2000 IU/day in supplement form) can be harmful.
For more information on vitamin D, return to Home Page and click on “Vitamins and Minerals”
Dosage: the best available data indicates that a daily supplemental dose of 800 IU per day is optimal from the standpoint of increasing BMD, preventing falls, and increasing strength. Meta-analyses of trials using 400 versus 800 IU per day suggest that 800 IU per day is more effective than 400 IU per day (see specifics above); one trial comparing 880 IU per day with 1600 IU per day did not show any added bone or muscle benefit from the higher dose (see specifics above).
Vitamin E
Gamma tocopherol, one of the 8 biochemical forms of vitamin E may be beneficial for bone, as high levels of gamma tocopherol are associated in postmenopausal women with high levels of bone-specific alkaline phosphatase (BAP), a marker of bone formation.
High alpha tocopherol intake (the form of vitamin E in many supplements and multivitamins) may be detrimental to bone, as a high alpha tocopherol to gamma tocopherol ratio is associated is inversely associated with bone-specific alkaline phosphatase (BAP) levels (J Bone Miner Res. 2012. 27. 1368-1380).
Vitamin K
Catalyzes a structural change in osteocalcin, a protein in bone, such that the osteocalcin attracts calcium, enhancing mineralization of bone. Matrix gamma-carboxyglutamic acid protein and protein S are other vitamin K-dependent proteins in bone.
Protects osteoblasts from apoptosis in cell culture (J Lab Clin Med. 2000. 136. 181-193), and (in mice) causes mature osteoclasts to undergo apoptosis (J Nutr Sci Vitaminol. 1999. 45. 501-507).
Vitamin K2 inhibits formation of PGE2, an inflammatory eicosanoid, in vitro (J Bone Miner Res. 1993. 8. 535-542) and in cell culture (Biochem Pharmacol. 1993. 46. 1355-1362). Vitamin K1 does NOT have this effect (Bone. 1995. 16. 179-184).
Protects against corticosteroid induce bone loss (Endocr J. 2001. 48. 11-18; Am J Kidney Dis. 2004. 48. 11-18).
Low circulating vitamin K is correlated with an osteoporosis (J Clin Endocrinol Metab. 1985. 60. 1268-1269).
Vitamin K1
In the ECKO trial, 5 mg daily vitamin K1 for 2-4 years did not protect against age-related BMD decline in postmenopausal women, but significantly fewer women in the vitamin K1 group had fractures (PLoS Med. 2008. 5. e196).
A systematic review and meta-analysis of 13 RCTs, all longer than 6 months in duration, 7 of which reported data on fractures, found that supplementation with phytonadione (1 – 10 mg/day) and menaquinone-4 (15 – 45 mg/day) reduces bone loss, and that supplementation with menaquinone-4 is protective against fractures. These 13 trials varied in size from 20 participants to 241 participants, and some included co-supplementation with other vitamins and minerals. NOTE that most of these trials were conducted in Japanese women (Cockayne S et al. Vitamin K and the Prevention of Fractures: Systematic Review and Meta-analysis of Randomized Controlled Trials. Arch Intern Med. 2006. 166. 1256-1261).
Vitamin K2 as menaquinone-4 (MK-4)
A systematic review and meta-analysis of 13 RCTs, all longer than 6 months in duration, 7 of which reported data on fractures, found that supplementation with phytonadione (1 – 10 mg/day) and menaquinone-4 (15 – 45 mg/day) reduces bone loss, and that supplementation with menaquinone-4 is protective against fractures. These 13 trials varied in size from 20 participants to 241 participants, and some included co-supplementation with other vitamins and minerals. NOTE that most of these trials were conducted in Japanese women (Cockayne S et al. Vitamin K and the Prevention of Fractures: Systematic Review and Meta-analysis of Randomized Controlled Trials. Arch Intern Med. 2006. 166. 1256-1261).
In a 2 year RCT of 200 ambulatory women (average age 78 years) with Alzheimer’s, randomized to receive 45 mg/day of menaquinone-4 (MK4), 1000 IU/day of vitamin D and 600 mg/day of calcium, versus placebo, there were 22 fractures in the control group, as compared with only 3 fractures in the treatment group. In the group taking MK-4, calcium, and vitamin D, there were 86% fewer non-vertebral fractures (p = 0.0003) and 87% fewer hip fractures (p = 0.0022) compared to the control group. There was no significant difference in the number of falls between the groups (Bone. 2005; 36:61-68).
Vitamin K2 as menaquinone-7 (MK-7)
180 mcg daily effective in reducing bone loss at the lumbar spine and femoral neck (but not at the total hip), based on a 3 year RCT of 244 healthy postmenopausal women (Osteoporosis Int. 2013. 24. 2499-2507).
Negative study: 375 mcg daily significantly decreased age-related deterioration in trabecular microarchitecture in a 12 month RCT of 148 postmenopausal women. However, no effect at one year on BMD (Eur J Endocrinol. 2016. 175. 541-549), and when the data was analyzed in these women at 3 years of follow-up, there were no significant differences in BMD (Oteoporosis Int. 2021. 32. 185-191).
Note MK-7 is the form of vitamin K2 in natto; MK-7 has greater biological activity and a longer half-life than MK-4 (Gaby AR. Townsend Letter. February/March 2014. 44).
Beware, in a RCT of 68 patients with diabetes and cardiovascular disease, intake of 360 mcg/day of MK-7 was associated with a nonsignificant increase in arterial calcification of the femoral artery (Zwakenberg SR et al. Am J Clin Nutr. Epub 8/16/19).
Beware, in a RCT of 48 patients with ESRD, on hemodialysis, intake of 360 mcg/day of MK-7 was associated with a nonsignificant increase in coronary artery calcification (Clin Kidney J. 2021. 14. 2114-2123).
Negative trials too, though (inconsistent results in clinical trials might be due to a confounding effect of vitamin D status).
A 3 year RCT among 325 postmenopausal women receiving either placebo or 45 mg/day of vitamin K2 (MK-4, menatetrenone) showed benefit with regard to bone mineral content (BMC) and femoral neck width (FMW), but not BMD. These results presumably translate into an improvement in strength (Osteoporosis Int. 2007. 18. 963-972). The beneficial effect of MK-4 on bone health may be due more to its side chain rather than its vitamin K activity, which may explain why pharmacological doses are necessary to achieve benefit (Gaby AR. Townsend Letter. February/March 2014. 44).
A 1 year trial in 381 postmenopausal North American women failed to show benefit of supplementation with either 1 mg/day vitamin K1 or 45 mg/day of MK-4, as compared with placebo (J Bone Min Res. 2009. 24. 983-991)..
A one year trial of MK-7 at a dose of 360 mcg/day in early postmenopausal women failed to show significant improvement in BMD (Osteoporosis Int. 2010. 21. 1731-1740).
An updated systematic review and meta-analysis of randomized controlled trials reported no evidence that vitamin K affects bone density or vertebral fracture risk in postmenopausal women and the evidence confirming a reduction in clinical fractures was deemed insufficient (Osteoporos Int 2019;30:1543-1559).
Consider a minimum supplemental dose of 100-500 mcg a day, ideally a mixture of vitamins K1 and K2 (BEWARE if on coumadin).
Dietary sources of vitamin K1 are green leafy vegetables and dietary sources of vitamin K2 are organ meats, egg yolks, fermented dairy products, and natto (a fermented soy product).
Zinc
Enhances the biochemical actions of vitamin D.
Important for the synthesis of osteoblasts and osteoclasts, as well as various proteins found in bone tissue.
Food sources include poultry, meat, whole grains.
Consider a supplemental dose of 10-30 mg a day.
References:
Gaby, Alan. Preventing and Reversing Osteoporosis. Prima Publishing. 1994.
Gaby AR and Wright JV. Nutrients and Osteoporosis. J Nutr Med. 1990. 1. 63-70.
Weil, Andrew. The Best Nutrients for Stronger Bones. Self Healing. March, 2005. 4-5.
Pizzorno, Joseph. Environmental Toxins Are a Major Cause of Bone Loss. IMCJ. 20[1]. 10/-17.
Resources:
Determine the approximate risk of hip fracture using a calculator posted at https://www.sheffield.ac.uk/FRAX/tool.aspx?country=9
Page Updated July 23 2024