Emerging Issues in Osteoporosis

Background

Osteoporosis and fragility fractures affect a large proportion of the population and have significant health and economic consequences. This thesis addresses several emerging questions regarding bone metabolism and the entity of osteoporosis, specifically:

How is bone mineral homeostasis related to energy metabolism and cardiovascular health?
By what mechanisms do certain disease states and medications contribute to the development of secondary osteoporosis?
Why do different tools used to estimate fracture risk sometimes give discordant results for the same patient, and how should these be addressed in clinical practice?
How can we better understand the side effect profiles of osteoporosis treatments, and develop strategies to mitigate adverse effects?

Methods

Six studies are described herein:

An analysis of relationships between circulating parathyroid hormone (PTH), cardiometabolic risk factors, and bone mineral density (BMD) in healthy men
An assessment of associations between phosphate and adiposity in three cohorts, and between fibroblast growth factor 23 (FGF23) and weight in a fourth cohort
A meta-analysis of randomized controlled trials (RCTs) assessing the effects of thiazolidinedione (TZD) medications on BMD and bone turnover
4An assessment of the effects of patient characteristics on absolute fracture risk estimates generated by the FRAX and Garvan fracture risk calculators
A crossover RCT evaluating the acute effects of calcium supplementation on blood pressure in postmenopausal women
A RCT assessing the effect of oral dexamethasone on prevention of the acute phase response (APR) following administration of zoledronic acid

Results & Conclusions

Results and their implications are summarized as follows:

PTH was positively associated with markers of cardiometabolic risk, including measures of adiposity and coronary artery calcification, but not with BMD. Adiposity may represent a cause of secondary hyperparathyroidism.
Serum phosphate was inversely associated with adiposity, independent of PTH. FGF23 and body weight were correlated, suggesting that FGF23 may mediate the relationship between phosphate and adiposity.
TZDs were associated with modest declines in BMD with no reversal after discontinuation. Avoidance of TZDs in those at high fracture risk may be prudent.
Estimates of fracture risk were higher, on average, with Garvan than FRAX. However, using a 3% ten-year hip fracture risk as a treatment threshold, the calculators were in agreement in 75% of cases. It is reassuring that the calculators often agree, but important to recognize that each incorporates different risk factors.
Supplementation with calcium as citrate resulted in attenuation of normal diurnal reductions in systolic blood pressure compared to placebo. Calcium supplements may work via this mechanism to increase cardiovascular risk.
Compared to placebo, a single dose of oral dexamethasone did not reduce the likelihood or severity of APR following zoledronic acid infusion. A higher dose or longer dosing interval may be required.

Year	Entry
2000	Delmas PD, Eastell R, Garnero P, Seibel MJ, Stepan J; Committee of Scientific Advisors of the International Osteoporosis Foundation. The use of biochemical markers of bone turnover in osteoporosis. Osteoporos Int. December 2000;11(suppl 6):S2-S17.
2017	Anastasilakis AD, Polyzos SA, Makras P, Aubry-Rozier B, Kaouri S, Lamy O. Clinical features of 24 patients with rebound-associated vertebral fractures after denosumab discontinuation: systematic review and additional cases. J Bone Miner Res. June 2017;32(6):1291-1296.
1994	Kanis JA, Melton LJ III, Christiansen C, Johnston CC, Khaltaev N. The diagnosis of osteoporosis. J Bone Miner Res. August 1994;9(8):1137-1141.
2014	Solomon DH, Johnston SS, Boytsov NN, McMorrow D, Lane JM, Krohn KD. Osteoporosis medication use after hip fracture in U.S. patients between 2002 and 2011. J Bone Miner Res. September 2014;29(9):1929-1937.
2007	Center JR, Bliuc D, Nguyen TV, Eisman JA. Risk of subsequent fracture after low-trauma fracture in men and women. JAMA. January 24, 2007;297(4):387-394.
2001	NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA. February 14, 2001;285(6):785-795.
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Year

Entry

2000

Delmas PD, Eastell R, Garnero P, Seibel MJ, Stepan J; Committee of Scientific Advisors of the International Osteoporosis Foundation. The use of biochemical markers of bone turnover in osteoporosis. Osteoporos Int. December 2000;11(suppl 6):S2-S17.

2017

Anastasilakis AD, Polyzos SA, Makras P, Aubry-Rozier B, Kaouri S, Lamy O. Clinical features of 24 patients with rebound-associated vertebral fractures after denosumab discontinuation: systematic review and additional cases. J Bone Miner Res. June 2017;32(6):1291-1296.

1994

Kanis JA, Melton LJ III, Christiansen C, Johnston CC, Khaltaev N. The diagnosis of osteoporosis. J Bone Miner Res. August 1994;9(8):1137-1141.

2014

Solomon DH, Johnston SS, Boytsov NN, McMorrow D, Lane JM, Krohn KD. Osteoporosis medication use after hip fracture in U.S. patients between 2002 and 2011. J Bone Miner Res. September 2014;29(9):1929-1937.

2007

Center JR, Bliuc D, Nguyen TV, Eisman JA. Risk of subsequent fracture after low-trauma fracture in men and women. JAMA. January 24, 2007;297(4):387-394.