Osteopenia, osteoporosis, and non-specific osteoarticular pain

A challenging picture

According to a study carried out in 2001 [1], 9.4% of women over forty (i.e., since a very young age) and 11.8% of men over sixty are affected by osteoporosis. The numbers increase considerably if referred to osteopenia (for the same population groups the figure is 47.2% for women and 46.1% for men), and even more so in proportion to the age of the patients’ sample considered. This figure points out a major problem, which is not easy to solve.
The guidelines [2,3] base their approach to this disease mainly on the intake of calcium and vitamin D, estrogens, bisphosphonates (for glucocorticoid-induced osteoporosis), but focus primarily on prevention at a younger age. Unfortunately, it is not uncommon for these therapeutic strategies to fail to achieve the desired results, mainly because of endocrine-metabolic conditions that limit their applicability, and even lead to a series of side effects due to the therapies themselves.
In order to identify the most effective therapeutic strategy, it is first of all necessary to understand the main reasons for the ongoing bone demineralization, given that they may be different and not be solved by a single therapy.

Understanding bone metabolism

The bone structure [4-7] is composed of highly mineralized connective tissue (mineral substance makes up about 70% of bone), and is crossed by the necessary blood and lymphatic vessels. Bone cells are also part of the organic substance in the bone, which is mostly type 1 collagen, and are involved in the various stages of bone metabolism. These cells fall into two basic categories:

  • osteoclasts, large, multi-nucleated cells responsible for bone decomposition; they attach to the mineralized structure and are able to remove it through acidification and protein digestion, by breaking down the minerals (calcium Ca and phosphorus P) from the bone matrix;
  • osteoblasts, on the other hand, are cells capable of secreting new protein fibrils (collagen) onto which minerals will then be fixed.


Figure 1: main interactions involved in bone metabolism

These cells do not act on their own, they move in groups called BMUs (Basic Multicellular Units), consisting essentially of a front of osteoclasts followed by a certain number of osteoblasts. The prevalence of the activity of one of these two types of cells is the main driver for differentiating the growth, maintenance (remodeling) and demineralization phases of the skeleton. The maximum level of bone density is usually reached around twenty years of age, while after thirty it generally starts to decrease.

Figure 2: schematic representation of bone cell balancing

The balance of these antagonistic processes depends on several factors that can influence the time of cell apoptosis (the life span of osteoclasts is generally much shorter than that of osteoblasts) or the formation of new osteoblasts and osteoclasts.

Figure 3: BMU activation

During their bone remodeling activity, osteoblasts can get stuck in the matrix formed by themselves, thus evolving into osteocytes: these are cells that, through long cytoplasmic membrane outgrowths, form an exchange network running through the bone tissue which can communicate with both the bone marrow and the BMUs (e.g. to stimulate remodeling of a particular bone fragment).
The bone tissue that does not undergo remodeling is generally protected by a micro-layer of collagen, surrounded by a layer of bone lining cells (i.e., cells derived from inactivated osteoblasts): this organic material prevents osteoclasts from adhering to the mineralized surface and is possibly removed by the lining cells which, through the mediation of osteocytes, can be stimulated to produce collagenase (which degrades type 1 and 2 collagen).

Changes in bone density

The decrease in bone density is a process that begins between thirty and forty years of age in both men and women, due to an increasing disproportion in the number of processes involved in bone tissue regeneration that are characterized by higher osteoclastic activity. In most cases this development is not related to a low calcium intake, but rather to other factors, mainly endocrine and metabolic ones, which can influence osteoblast and osteoclast activity. However, it is the predominance of osteoclasts over osteoblasts that leads to gradual bone demineralization (and consequently to bone fragility).

Endocrine factors

Among the factors that are most commonly involved in the imbalance between the action of osteoclasts and osteoblasts – in addition to sex hormone (estrogen, testosterone) deficiency – is a chronic excess of glucocorticoids [8-15] (both endogenous and exogenous; BIA-ACC - Flat Low/High HPA axis index).

Figure 4: glucocorticoids and bone metabolism (BIA-ACC - Flat Low/High HPA axis index)

There is evidence of the effects that this excess triggers on bone metabolism, through mechanisms that are both direct on bone cells and mediated by local and systemic interactions with hormones, growth factors and cytokines.

Figura 5: glucocorticoids and RANKL/OPG/RANK binding

At an endocrine level, glucocorticoids reduce intestinal calcium absorption while increasing renal calcium clearance, thus causing hypocalcemia. This condition is associated with increased osteoclast activation and hence to an increased bone resorption (research will have to clarify whether this is due to glucocorticoid-induced hyperparathyroidism or to increased PTH sensitivity by osteoblasts, which would react to this hormone by activating the osteoclasts). Glucocorticoids also inhibit GH secretion and sex hormone synthesis, while increased glucocorticoids are associated with an increased collagenase expression, that has negative effects on organic bone matter (see HPA axis for more details: Insomnia, mood disorders, anxiety, melancholy, depression, MUS, panic attacks).
Glucocorticoids also have direct effects on bone cells through the RANKL/OPG cytokine system [7,16] by increasing the expression of the former and decreasing that of the latter, and thus promoting the binding of RANKL cytokines (expressed on osteoblast membranes) to RANK receptors (on the membranes of osteoclast progenitors); this binding stimulates the differentiation and activation of osteoclasts and inhibits their apoptosis (programmed cell death).
The increase in glucocorticoids also inhibits the osteoblast differentiation factor, thus reducing the bone regeneration activity, and increases osteoblast and osteocyte apoptosis as well. Osteocyte apoptosis also plays a key role in bone fragility, since osteocytes – as already seen – are involved in BMU activation and bone remodeling processes.
The effects described above are due both to exogenous glucocorticoid excesses [9,14] (and should therefore be particularly taken into account in patients taking glucocorticoids for therapeutic purposes) and to endogenous ones. Among the factors that are involved in chronic excess cortisol and the related circadian rhythm shift (BIA-ACC - Flat Low/High HPA axis index)there are the presence of chronic inflammatory processes, chronic stress on the HPA axis and poor nutrition [26-29].
High-titer EPA+DHA omega-3 fatty acids have been shown to reduce the expression of RANKL cytokines and increase OPG [17-21], thereby decreasing osteoclast activation; high-titer EPA+DHA omega-3 fatty acids intake is also associated with a reduction in the concentration of proinflammatory cytokines (e.g. IL-6 and TNF-α), so the effects of these fatty acids contribute in several directions to reducing bone absorption. Recent studies [22,23] have also reported that certain hop flavonoids (Humulus Lupulus L.), in particular xanthohumol, are able to interact selectively with estrogen receptors and exert an estrogen-like activity on bone metabolism (thus reducing demineralization), without producing the side effects of hormone therapies (several publications report an increased risk of breast and uterine cancer), while also showing a protective effect against these problems (see high titration EPA+DHA+Humulus Lupulus L. supplementation).

Metabolic factors

Figure 6: acidosis and bone metabolism (see supplementation with buffer systems)

Bone remodeling is not only instrumental in tissue regeneration and in the adaptation of the skeletal structure to the mechanical stresses to which it is subject, it is also an essential process for calcium homeostasis, as bone tissue is the body’s main calcium reservoir. However, the balance with free ionized calcium in the plasma (and its possible deficiency) is not the main aspect to be considered from this viewpoint: it is known that bone tissue plays a fundamental role in balancing body pH, as it is itself a buffer system against acidosis [24,25]. The decalcification produced to preserve body pH can obviously lead to increased bone fragility and hypercalcemia.
Therefore, from a therapeutic standpoint, in order to cope with such a situation it is necessary to take proper supplementation with phosphate and bicarbonate buffer systems (see supplementation with buffer systems): restoring the pH becomes a priority [30-31] over replenishing calcium, given that calcium may already have excessive plasma concentrations due to the ongoing bone demineralization.

Why should a therapy be instituted?

If the bone tissue is subject to demineralization for one or more of the aforementioned reasons, it will be necessary to treat the patient to correct this trend prior to considering the usual calcium and vitamin D supplementation (which may not be necessary), as the excess of these components, deprived of the systemic conditions for bone tissue recovery, would easily lead to side effects such as soft tissue calcifications or kidney stones, and would not be able to limit the ongoing bone mineral loss.

Figure 7: side effects of a therapy that does not address endocrine and metabolic aspects

Authors: Dario Boschiero - Date: 14/12/2020

Attention: these contents can be freely used for personal learning purposes only. The use is regulated by Law No. 633/1941 and subsequent amendments, as well as by the copyright and patent legislation in force. Any use for commercial and profit-making purposes is forbidden.


  1. G. Farchi, Osteoporosi. Le dimensioni del problema in Italia, Laboratorio di Epidemiologia e Biostatistica – Istituto Superiore di Sanità, 2001;
  2. Linee guida per la prevenzione dell'osteoporosi, Ministero della salute;
  3. Osteoporosi: una malattia sociale. Spidemiologia, costi assistenziali, interventi terapeutici, Istituto Superiore di Sanità;
  4. Russell RG, Espina B, Hulley P, Bone biology and the pathogenesis of osteoporosis, Curr Opin Rheumatol. 2006 Jun;18 Suppl 1:S3-10;
  5. Downey PA, Siegel MI, Bone biology and the clinical implications for osteoporosis, Phys Ther. 2006 Jan;86(1):77-91;
  6. Raisz LG, Pathogenesis of osteoporosis: concepts, conflicts, and prospects, J Clin Invest. 2005 Dec;115(12):3318-25.
  7. Manolagas SC, Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis, Endocr Rev. 2000 Apr;21(2):115-37;
  8. Shaker JL, Lukert BP, Osteoporosis associated with excess glucocorticoids, Endocrinol Metab Clin North Am. 2005 Jun;34(2):341-56;
  9. Reynolds RM, Dennison EM, Walker BR, Syddall HE, Wood PJ, Andrew R, Phillips DI, Cooper C, Cortisol secretion and rate of bone loss in a population-based cohort of elderly men and women, Calcif Tissue Int. 2005 Sep;77(3):134-8. Epub 2005 Sep 8;
  10. Cooper MS, Syddall HE, Fall CH, Wood PJ, Stewart PM, Cooper C, Dennison EM, Circulating cortisone levels are associated with biochemical markers of bone formation and lumbar spine BMD: the Hertfordshire Cohort Study, Clin Endocrinol (Oxf). 2005 Jun;62(6):692-7;
  11. Angeli A, Osella G, Reimondo G, Terzolo M, Glucocorticoid-induced osteoporosis: recent findings, Ann Ital Med Int. 2000 Jan-Mar;15(1):47-55;
  12. Manelli F, Giustina A, Glucocorticoid-induced osteoporosis, Trends Endocrinol Metab. 2000 Apr;11(3):79-85;
  13. Dennison E, Hindmarsh P, Fall C, Kellingray S, Barker D, Phillips D, Cooper C, Profiles of endogenous circulating cortisol and bone mineral density in healthy elderly men, J Clin Endocrinol Metab. 1999 Sep;84(9):3058-63;
  14. Tomita A, Glucocorticoid-induced osteoporosis--mechanisms and preventions, Nippon Rinsho. 1998 Jun;56(6):1574-8;
  15. Ziegler R, Kasperk C, Glucocorticoid-induced osteoporosis: prevention and treatment, Steroids. 1998 May-Jun;63(5-6):344-8;
  16. Di Munno O, Delle Sedie A, Osteoporosi da glucocorticoidi e malattie reumatiche. Patogenesi, prevenzione e trattamento, Reumatismo. 2006 Jan-Mar;58(1):11-21;
  17. Fernandes G, Lawrence R, Sun D, Protective role of n-3 lipids and soy protein in osteoporosis, Prostaglandins Leukot Essent Fatty Acids. 2003 Jun;68(6):361-72;
  18. Darlington LG, Stone TW, Antioxidants and fatty acids in the amelioration of rheumatoid arthritis and related disorders, Br J Nutr. 2001 Mar;85(3):251-69;
  19. Calder PC, Zurier RB, Polyunsaturated fatty acids and rheumatoid arthritis, Curr Opin Clin Nutr Metab Care. 2001 Mar;4(2):115-21;
  20. Kettler DB, Can manipulation of the ratios of essential fatty acids slow the rapid rate of postmenopausal bone loss?, Altern Med Rev. 2001 Feb;6(1):61-77;
  21. Bhattacharya A, Rahman M, Banu J, Lawrence RA, McGuff HS, Garrett IR, Fischbach M, Fernandes G, Inhibition of osteoporosis in autoimmune disease prone MRL/Mpj-Fas(lpr) mice by N-3 fatty acids, J Am Coll Nutr. 2005 Jun;24(3):200-9;
  22. Effenberger KE, Johnsen SA, Monroe DG, Spelsberg TC, Westendorf JJ, Regulation of osteoblastic phenotype and gene expression by hop-derived phytoestrogens, J Steroid Biochem Mol Biol. 2005 Sep;96(5):387-99. Epub 2005 Jul 12;
  23. Tobe H, Muraki Y, Kitamura K, Komiyama O, Sato Y, Sugioka T, Maruyama HB, Matsuda E, Nagai M, Bone resorption inhibitors from hop extract, Biosci Biotechnol Biochem. 1997 Jan;61(1):158-9;
  24. New SA, Intake of fruit and vegetables: implications for bone health, Proc Nutr Soc. 2003 Nov;62(4):889-99. Review. Erratum in: Proc Nutr Soc. 2004 Feb;63(1):187;
  25. Morselli B, Neuenschwander B, Perrelet R, Lippuner K, Osteoporosis diet, Ther Umsch. 2000 Mar;57(3):152-60;
  26. D. Boschiero, Sintomi vaghi ed aspecifici. Stress dell'asse HPA e infiammazione cronica;
  27. D. Boschiero, Nutrizione clinica. Nuove applicazioni pratiche diagnostiche e terapeutiche;
  28. Scheda tecnica dispostivo medicale TomEEx, algoritmi “processi infiammatori” e “n.i.e. neuroimmunoendocrino”;
  29. Scheda tecnica dispositivo medicale RegMatEx, modulazione potenziale di membrana;
  30. D. Boschiero, Approfondimenti sul pH tissutale extracellulare. Sistemi tampone fosfato e bicarbonato;
  31. Scheda tecnica dispositivo medicale TomEEx, algoritmo “acidosi tissutale extracellulare”.